Biochemistry, Genetics and Molecular Biology › Molecular Biology

Cancer therapeutics and mechanisms

Works Count: 47235

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This cluster of papers focuses on the structure, function, inhibition, and genetic variants of DNA topoisomerases, particularly their roles in chemotherapy, the mechanism of action of specific inhibitors such as irinotecan and quinolones, and their impact on genomic stability. The papers also explore the potential use of genetic variants in predicting drug toxicity and treatment outcomes.

Keywords

Topoisomerases; DNA; Inhibitors; Chemotherapy; Genetic Variants; Irinotecan; Quinolones; Anticancer Drugs; Enzyme Mechanism; Genomic Stability

Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11.

1991-08-15

Yasuyoshi Kawato , Masashi Aonuma , Yasuhide Hirota +2 more

It is known that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), a semisynthesized derivative of camptothecin (CPT), has a potent antitumor activity in vivo, but 7-ethyl-10-hydroxycamptothecin (SN-38), a metabolite of CPT-11, shows much stronger cytotoxicity … It is known that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), a semisynthesized derivative of camptothecin (CPT), has a potent antitumor activity in vivo, but 7-ethyl-10-hydroxycamptothecin (SN-38), a metabolite of CPT-11, shows much stronger cytotoxicity in vitro than CPT-11. In this study, we demonstrated that the relaxation of SV40 DNA plasmids by type I DNA topoisomerase prepared from P388 murine leukemia cells was inhibited by 50% by SN-38 at approximately 1 microM, although CPT-11 at 1 mM slightly inhibited the relaxation. SN-38 and CPT showed strong, time-dependent inhibitory activity against DNA synthesis of P388 cells. However, CPT-11 weakly inhibited DNA synthesis independently of time with coincident inhibition of the total thymidine uptake by the cells. By alkaline and neutral elution assays, it was demonstrated that SN-38 caused much more frequent DNA single-strand breaks in P388 cells than did CPT-11. The same content of SN-38 and a similar frequency of single-strand breaks were detected in the cells treated with SN-38 at 0.1 microM or with CPT-11 at 100 microM. Therefore, single-strand breaks by CPT-11 seem to be due to SN-38 produced from CPT-11 in cells. These results indicate that CPT-11 itself possesses a marginal antiproliferative effect but that SN-38 plays an essential role in the mechanism of action of CPT-11.

Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.

1984-07-01

K M Tewey , G L Chen , Eric M. Nelson +1 more

Many intercalative antitumor drugs have been shown to induce reversible protein-linked DNA breaks in cultured mammalian cells.Using purified mammalian DNA topoisomerase 11, we have demonstrated that the antitumor drugs ellipticine … Many intercalative antitumor drugs have been shown to induce reversible protein-linked DNA breaks in cultured mammalian cells.Using purified mammalian DNA topoisomerase 11, we have demonstrated that the antitumor drugs ellipticine and 2-methyl-S-h~droxyellipticine (2-Me-S-OH-E+) can produce reversible protein-linked DNA breaks in vitro.2-Me-9-OH-E+ which is more cytotoxic toward L1210 cells and more active against experimental tumors than ellipticine is also more effective in stimulating DNA cleavage in vitro.Similar to the effect of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) on topoisomerase I1 in vitro, the mechanism of DNA breakage induced by ellipticines is most likely due to the drug stabilization of a cleavable complex formed between topoisomerase I1 and DNA.Protein denaturant treatment of the cleavable complex results in DNA breakage and covalent linking of one topoisomerase I1 subunit to each 5'-end of the cleaved DNA.Cleavage sites on pBR322 DNA produced by ellipticine or 2-Me-9-OH-E+ treatment mapped at the same positions.However, many of these cleavage sites are distinctly different from those produced by the antitumor drug m-AMSA which also targets at topoisomerase 11.Our results thus suggest that although mammalian DNA topoisomerase 11 may be a common target of these antitumor drugs, drug-DNA-topoisomerase interactions for different antitumor drugs may be different.

Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I.

1985-11-01

Y H Hsiang , Robert Hertzberg , Sidney M. Hecht +1 more

Camptothecin, a cytotoxic drug, is a strong inhibitor of nucleic acid synthesis in mammalian cells and a potent inducer of strand breaks in chromosomal DNA. Neither the equilibrium dialysis nor … Camptothecin, a cytotoxic drug, is a strong inhibitor of nucleic acid synthesis in mammalian cells and a potent inducer of strand breaks in chromosomal DNA. Neither the equilibrium dialysis nor the unwinding measurement indicates any interaction between camptothecin and purified DNA. However, camptothecin induces extensive single strand DNA breaks in reactions containing purified mammalian DNA topoisomerase I. DNA breakage in vitro is immediate and reversible. Analyses of camptothecin-induced DNA breaks show that topoisomerase I is covalently linked to the 3' end of the broken DNA. In addition, camptothecin inhibits the catalytic activity of mammalian DNA topoisomerase I. We propose that camptothecin blocks the rejoining step of the breakage-reunion reaction of mammalian DNA topoisomerase I. This blockage results in the accumulation of a cleavable complex which resembles the transient intermediate proposed for eukaryotic DNA topoisomerase I. The inhibition of nucleic acid synthesis and the induction of DNA strand breaks observed in vivo may be related to the formation of this drug-induced cleavable complex.

Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin.

1989-09-15

Y H Hsiang , M G Lihou , Leroy F. Liu

Camptothecin, which induces an unusual type of DNA damage by trapping cellular topoisomerase I on chromosomal DNA in the form of drug-enzyme-DNA cleavable complexes, inhibits DNA synthesis and specifically kills … Camptothecin, which induces an unusual type of DNA damage by trapping cellular topoisomerase I on chromosomal DNA in the form of drug-enzyme-DNA cleavable complexes, inhibits DNA synthesis and specifically kills S-phase cells. Cotreatment of L1210 cells with aphidicolin, which is an inhibitor of replicative DNA polymerases, completely abolished camptothecin cytotoxicity, suggesting the involvement of DNA replication in camptothecin cytotoxicity. In order to study the role of DNA replication in drug action, a cell-free SV40 DNA replication system was used in the present study. Camptothecin inhibited SV40 DNA replication in this cell-free system only in the presence of topoisomerase I. Addition of excess purified calf thymus DNA topoisomerase I to this extract system in the presence of camptothecin resulted in severe inhibition of SV40 DNA replication and the accumulation of linearized replication products, which contained covalently bound DNA topoisomerase I. We propose that the collision between moving replication forks and camptothecin-stabilized topoisomerase I-DNA cleavable complexes results in fork arrest and possibly fork breakage, which are lethal to proliferating cells.

The mechanism of topoisomerase I poisoning by a camptothecin analog

2002-11-08

Bart L. Staker , Kathryn A. Hjerrild , M.D. Feese +3 more

We report the x-ray crystal structure of human topoisomerase I covalently joined to double-stranded DNA and bound to the clinically approved anticancer agent Topotecan. Topotecan mimics a DNA base pair … We report the x-ray crystal structure of human topoisomerase I covalently joined to double-stranded DNA and bound to the clinically approved anticancer agent Topotecan. Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor. The structure can explain several of the known structure–activity relationships of the camptothecin family of anticancer drugs and suggests that there are at least two classes of mutations that can produce a drug-resistant enzyme. The first class includes changes to residues that contribute to direct interactions with the drug, whereas a second class would alter interactions with the DNA and thereby destabilize the drug-binding site.

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Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k

1997-06-15

Harold B.J. Jefferies , Stefano Fumagalli , Patrick B. Dennis +3 more

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Nalidixic acid resistance: A second genetic character involved in DNA gyrase activity

1977-11-01

Martin Gellert , Kiyoshi Mizuuchi , M H O'Dea +2 more

ATP-dependent DNA supercoiling catalyzed by Escherichia coli DNA gyrase was inhibited by oxolinic acid, a compound similar to but more potent than nalidixic acid and a known inhibitor of DNA … ATP-dependent DNA supercoiling catalyzed by Escherichia coli DNA gyrase was inhibited by oxolinic acid, a compound similar to but more potent than nalidixic acid and a known inhibitor of DNA replication in E. coli . The supercoiling activity of DNA gyrase purified from nalidixic acid-resistant mutant ( nalA R ) bacteria was resistant to oxolinic acid. Thus, the nalA locus is responsible for a second component needed for DNA gyrase activity in addition to the component determined by the previously described locus for resistance to novobiocin and coumermycin ( cou ). Supercoiling of λ DNA in E. coli cells was likewise inhibited by oxolinic acid, but was resistant in the nalA R mutant. The inhibition by oxolinic acid of colicin E1 plasmid DNA synthesis in a cell-free system was largely relieved by adding resistant DNA gyrase. In the absence of ATP, DNA gyrase preparations relaxed supercoiled DNA; this activity was also inhibited by oxolinic acid, but not by novobiocin. It appears that the oxolinic acid-sensitive component of DNA gyrase is involved in the nicking-closing activity required in the supercoiling reaction. In the presence of oxolinic acid, DNA gyrase forms a complex with DNA, which can be activated by later treatment with sodium dodecyl sulfate and a protease to produce double-strand breaks in the DNA. This process has some similarities to the known properties of relaxation complexes.

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A simple phase-extraction assay for chloramphenicol acyltransferase activity

1988-07-01

Brian Seed , Jenq-Yunn Sheen

Drugging Topoisomerases: Lessons and Challenges

2012-12-21

Yves Pommier

Topoisomerases are ubiquitous enzymes that control DNA supercoiling and entanglements. They are essential during transcription and replication, and topoisomerase inhibitors are among the most effective and most commonly used anticancer … Topoisomerases are ubiquitous enzymes that control DNA supercoiling and entanglements. They are essential during transcription and replication, and topoisomerase inhibitors are among the most effective and most commonly used anticancer and antibacterial drugs. This review consists of two parts. In the first part ("Lessons"), it gives background information on the catalytic mechanisms of the different enzyme families (6 different genes in humans and 4 in most bacteria), describes the "interfacial inhibition" by which topoisomerase-targeted drugs act as topoisomerase poisons, and describes clinically relevant topoisomerase inhibitors. It generalizes the interfacial inhibition principle, which was discovered from the mechanism of action of topoisomerase inhibitors, and discusses how topoisomerase inhibitors kill cells by trapping topoisomerases on DNA rather than by classical enzymatic inhibition. Trapping protein–DNA complexes extends to a novel mechanism of action of PARP inhibitors and could be applied to the targeting of transcription factors. The second part of the review focuses on the challenges for discovery and precise use of topoisomerase inhibitors, including targeting topoisomerase inhibitors using chemical coupling and encapsulation for selective tumor delivery, use of pharmacodynamic biomarkers to follow drug activity, complexity of the response determinants for anticancer activity and patient selection, prospects of rational combinations with DNA repair inhibitors targeting tyrosyl-DNA-phosphodiesterases 1 and 2 (TDP1 and TDP2) and PARP, and the unmet need to develop inhibitors for type IA enzymes.

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Adriamycin-Induced DNA Damage Mediated by Mammalian DNA Topoisomerase II

1984-10-26

K M Tewey , Thomas C. Rowe , Liu Yang +2 more

Adriamycin (doxorubicin), a potent antitumor drug in clinical use, interacts with nucleic acids and cell membranes, but the molecular basis for its antitumor activity is unknown. Similar to a number … Adriamycin (doxorubicin), a potent antitumor drug in clinical use, interacts with nucleic acids and cell membranes, but the molecular basis for its antitumor activity is unknown. Similar to a number of intercalative antitumor drugs and nonintercalative epipodophyllotoxins (VP-16 and VM-26), adriamycin has been shown to induce single- and double-strand breaks in DNA. These strand breaks are unusual because a covalently bound protein appears to be associated with each broken phosphodiester bond. In studies in vitro, mammalian DNA topoisomerase II mediates DNA damage by adriamycin and other related antitumor drugs.

An atypical topoisomerase II from archaea with implications for meiotic recombination

1997-03-01

Agnès Bergerat , Bernard de Massy , Danielle Gadelle +3 more

Plant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata1,2

1966-08-01

Monroe E. Wall , Mansukh C. Wani , Clarence Cook +3 more

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPlant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata1,2Monroe E. Wall, M. C. Wani, C. E. … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPlant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata1,2Monroe E. Wall, M. C. Wani, C. E. Cook, Keith H. Palmer, A. T. McPhail, and G. A. SimCite this: J. Am. Chem. Soc. 1966, 88, 16, 3888–3890Publication Date (Print):August 1, 1966Publication History Published online1 May 2002Published inissue 1 August 1966https://doi.org/10.1021/ja00968a057Request reuse permissionsArticle Views5243Altmetric-Citations1718LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (409 KB) Get e-Alertsclose Get e-Alerts

Mechanism of action of nalidixic acid: Purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme

1977-11-01

Akio Sugino , Craig L. Peebles , Kenneth N. Kreuzer +1 more

A target protein for nalidixic and oxolinic acids in Escherichia coli , the nalA gene product (Pnal), was purified to homogeneity as judged by gel electrophoresis, using an in vitro … A target protein for nalidixic and oxolinic acids in Escherichia coli , the nalA gene product (Pnal), was purified to homogeneity as judged by gel electrophoresis, using an in vitro complementation assay. It is a dimer of identical 110,000-dalton subunits. A polypeptide of this molecular weight is uniquely induced by a λ nalA transducing phage, thereby showing that the purified Pnal is a product of the nalA gene. Nalidixic and oxolinic acids inhibit DNA gyrase activity and induce formation of a relaxation complex analogue. Treatment of the complex with sodium dodecyl sulfate causes a doublestrand break in the DNA substrate and the resulting linear molecule seems covalently bound to protein. Complex formation, unlike the introduction of supertwists, does not require ATP or relaxed circular DNA and is insensitive to novobiocin. DNA gyrase from a strain with a nalA mutation conferring drug resistance ( nalA r ) is 1/100 as sensitive to oxolinic and nalidixic acids with respect to inhibition of supertwisting and induction of the pre-linearization complex. Addition of Pnal restores drug sensitivity and stimulates DNA gyrase activity. DNA gyrase preparations and Pnal catalyze a third reaction sensitive to nalidixic and oxolinic acids, the ATP-independent relaxation of supertwister DNA. Relaxation by gyrase from nalA r cells is drug resistant. The nicking-closing activity is distinct from E. coli ω protein in several properties, including the ability to relax positively supertwisted DNA. We postulate that the nalA gene product occurs in two molecular forms, as Pnal and as a gyrase component. Both forms catalyze nicking-closing, and inhibition of this activity by nalidixic and oxolinic acids may account for the inhibition of DNA synthesis by these drugs.

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Mechanism of Quinolone Action and Resistance

2014-02-27

Katie J. Aldred , Robert J. Kerns , Neil Osheroff

Quinolones are one of the most commonly prescribed classes of antibacterials in the world and are used to treat a variety of bacterial infections in humans. Because of the wide … Quinolones are one of the most commonly prescribed classes of antibacterials in the world and are used to treat a variety of bacterial infections in humans. Because of the wide use (and overuse) of these drugs, the number of quinolone-resistant bacterial strains has been growing steadily since the 1990s. As is the case with other antibacterial agents, the rise in quinolone resistance threatens the clinical utility of this important drug class. Quinolones act by converting their targets, gyrase and topoisomerase IV, into toxic enzymes that fragment the bacterial chromosome. This review describes the development of the quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanistic basis for quinolone action against their enzyme targets. It will then discuss the following three mechanisms that decrease the sensitivity of bacterial cells to quinolones. Target-mediated resistance is the most common and clinically significant form of resistance. It is caused by specific mutations in gyrase and topoisomerase IV that weaken interactions between quinolones and these enzymes. Plasmid-mediated resistance results from extrachromosomal elements that encode proteins that disrupt quinolone-enzyme interactions, alter drug metabolism, or increase quinolone efflux. Chromosome-mediated resistance results from the underexpression of porins or the overexpression of cellular efflux pumps, both of which decrease cellular concentrations of quinolones. Finally, this review will discuss recent advancements in our understanding of how quinolones interact with gyrase and topoisomerase IV and how mutations in these enzymes cause resistance. These last findings suggest approaches to designing new drugs that display improved activity against resistant strains.

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Crystal Structures of Human Topoisomerase I in Covalent and Noncovalent Complexes with DNA

1998-03-06

Matthew R. Redinbo , Lance Stewart , Peter Kühn +2 more

Topoisomerases I promote the relaxation of DNA superhelical tension by introducing a transient single-stranded break in duplex DNA and are vital for the processes of replication, transcription, and recombination. The … Topoisomerases I promote the relaxation of DNA superhelical tension by introducing a transient single-stranded break in duplex DNA and are vital for the processes of replication, transcription, and recombination. The crystal structures at 2.1 and 2.5 angstrom resolution of reconstituted human topoisomerase I comprising the core and carboxyl-terminal domains in covalent and noncovalent complexes with 22–base pair DNA duplexes reveal an enzyme that “clamps” around essentially B-form DNA. The core domain and the first eight residues of the carboxyl-terminal domain of the enzyme, including the active-site nucleophile tyrosine-723, share significant structural similarity with the bacteriophage family of DNA integrases. A binding mode for the anticancer drug camptothecin is proposed on the basis of chemical and biochemical information combined with these three-dimensional structures of topoisomerase I–DNA complexes.

Molecular mechanisms of drug resistance

2005-01-01

DB Longley , PG Johnston

Abstract Resistance to chemotherapy limits the effectiveness of anti‐cancer drug treatment. Tumours may be intrinsically drug‐resistant or develop resistance to chemotherapy during treatment. Acquired resistance is a particular problem, as … Abstract Resistance to chemotherapy limits the effectiveness of anti‐cancer drug treatment. Tumours may be intrinsically drug‐resistant or develop resistance to chemotherapy during treatment. Acquired resistance is a particular problem, as tumours not only become resistant to the drugs originally used to treat them, but may also become cross‐resistant to other drugs with different mechanisms of action. Resistance to chemotherapy is believed to cause treatment failure in over 90% of patients with metastatic cancer, and resistant micrometastic tumour cells may also reduce the effectiveness of chemotherapy in the adjuvant setting. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanisms of drug resistance that operate to reduce drug sensitivity in cancer cells. Drug resistance can occur at many levels, including increased drug efflux, drug inactivation, alterations in drug target, processing of drug‐induced damage, and evasion of apoptosis. Advances in DNA microarray and proteomic technology, and the ongoing development of new targeted therapies have opened up new opportunities to combat drug resistance. We are now able to characterize the signalling pathways involved in regulating tumour cell response to chemotherapy more completely than ever before. This will facilitate the future development of rational combined chemotherapy regimens, in which the newer targeted therapies are used in combination with cytotoxic drugs to enhance chemotherapy activity. The ability to predict response to chemotherapy and to modulate this response with targeted therapies will permit selection of the best treatment for individual patients. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Targeting DNA topoisomerase II in cancer chemotherapy

2009-04-20

John L. Nitiss

Topoisomerase II is a structural component of mitotic chromosome scaffolds.

1985-05-01

William C. Earnshaw , Brian Halligan , Carol Cooke +2 more

We have obtained a polyclonal antibody that recognizes a major polypeptide component of chicken mitotic chromosome scaffolds. This polypeptide migrates in SDS PAGE with Mr 170,000. Indirect immunofluorescence and subcellular … We have obtained a polyclonal antibody that recognizes a major polypeptide component of chicken mitotic chromosome scaffolds. This polypeptide migrates in SDS PAGE with Mr 170,000. Indirect immunofluorescence and subcellular fractionation experiments confirm that it is present in both mitotic chromosomes and interphase nuclei. Two lines of evidence suggest that this protein is DNA topoisomerase II, an abundant nuclear enzyme that controls DNA topological states: anti-scaffold antibody inhibits the strand-passing activity of DNA topoisomerase II; and both anti-scaffold antibody and an independent antibody raised against purified bovine topoisomerase II recognize identical partial proteolysis fragments of the 170,000-mol-wt scaffold protein in immunoblots. Our results suggest that topoisomerase II may be an enzyme that is also a structural protein of interphase nuclei and mitotic chromosomes.

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Mechanisms of bleomycin-induced DNA degradation

1987-10-01

JoAnne Stubbe , John W. Kozarich

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMechanisms of bleomycin-induced DNA degradationJoAnne. Stubbe and John W. KozarichCite this: Chem. Rev. 1987, 87, 5, 1107–1136Publication Date (Print):October 1, 1987Publication History Published online1 May 2002Published inissue … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMechanisms of bleomycin-induced DNA degradationJoAnne. Stubbe and John W. KozarichCite this: Chem. Rev. 1987, 87, 5, 1107–1136Publication Date (Print):October 1, 1987Publication History Published online1 May 2002Published inissue 1 October 1987https://pubs.acs.org/doi/10.1021/cr00081a011https://doi.org/10.1021/cr00081a011research-articleACS PublicationsRequest reuse permissionsArticle Views2052Altmetric-Citations749LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

DNA topoisomerase II and its growing repertoire of biological functions

2009-04-20

John L. Nitiss

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Etoposide: four decades of development of a topoisomerase II inhibitor

1998-09-01

Kenneth R. Hande

Structure and mechanism of DNA topoisomerase II

1996-01-18

James M. Berger , S.J. Gamblin , Stephen C. Harrison +1 more

Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells

2003-03-01

Sonam Dolma , Stephen L. Lessnick , William C. Hahn +1 more

Supercoiling of the DNA template during transcription.

1987-10-01

Leroy F. Liu , J C Wang

Transcription of a right-handed double-helical DNA requires a relative rotation of the RNA polymerase and its nascent RNA around the DNA. We describe conditions under which the resistance to the … Transcription of a right-handed double-helical DNA requires a relative rotation of the RNA polymerase and its nascent RNA around the DNA. We describe conditions under which the resistance to the rotational motion of the transcription ensemble around the DNA can be large. In such cases, the advancing polymerase generates positive supercoils in the DNA template ahead of it and negative supercoils behind it. Mutual annihilation of the positively and negatively supercoiled regions may be prevented by anchoring points on the DNA to a large structure, or, in the case of an unanchored plasmid, by the presence of two oppositely oriented transcription units. In prokaryotes, DNA topoisomerase I preferentially removes negative supercoils and DNA gyrase (topoisomerase II) removes positive ones. Our model thus provides an explanation for the experimentally observed high degree of negative or positive supercoiling of intracellular pBR322 DNA when DNA topoisomerase I or gyrase is respectively inhibited. We discuss the implications of our model in terms of supercoiling regulation, DNA conformational transitions, and gene regulation in both prokaryotes and eukaryotes.

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DNA Topoisomerases and Their Poisoning by Anticancer and Antibacterial Drugs

2010-05-01

Yves Pommier , Elisabetta Leo , Hongliang Zhang +1 more

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Transformation of Aspergillus nidulans by using a trpC plasmid.

1984-03-01

Melanie Yelton , John E. Hamer , William E. Timberlake

We constructed a chimeric plasmid carrying a complete copy of the trifunctional trpC gene from the Ascomycete fungus Aspergillus nidulans. This plasmid, designated pHY201, replicates in Escherichia coli, where it … We constructed a chimeric plasmid carrying a complete copy of the trifunctional trpC gene from the Ascomycete fungus Aspergillus nidulans. This plasmid, designated pHY201, replicates in Escherichia coli, where it confers resistance to ampicillin and chloramphenicol and complements trpC mutants lacking phosphoribosylanthranilate isomerase activity. We used pHY201 to transform an A. nidulans trpC- strain to trpC+ at frequencies of greater than 20 stable transformants per microgram of DNA. Southern blot analysis of DNA from transformants showed that pHY201 DNA had integrated into the A. nidulans chromosomes in a majority of cases. Most of the integration events appeared to occur at the site of the trpC- allele of the recipient strain. In several instances, we succeeded in recovering pHY201, or derivatives thereof, from A. nidulans transformants by restriction endonuclease digestion of chromosomal DNA, ligation, and transformation of E. coli.

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A clinical review of bleomycin—a new antineoplastic agent

1973-04-01

Ronald H. Blum , Stephen K. Carter , Karl Agre

Bleomycin, a new antibiotic antineoplastic agent, has undergone extensive clinical trial. Data from 1,174 patients were reviewed and summarized by cell type. The most commonly used dose schedule was 15 … Bleomycin, a new antibiotic antineoplastic agent, has undergone extensive clinical trial. Data from 1,174 patients were reviewed and summarized by cell type. The most commonly used dose schedule was 15 mg/m2 twice a week intravenously. Significant response rates were achieved in patients with squamous cell carcinoma of various anatomical sites, lymphomas, and testicular carcinoma. Most responses were of 1 to 2 months' duration. Drug toxicities included significant skin and pulmonary complications and some degree of drug-induced pyrexia and nausea with vomiting. Rare insignificant bone marrow depression was encountered. The limitations of a retrospective clinical review of this type using uncontrolled pooled data from various patient populations were discussed. In conclusion, however, bleomycin appeared to be useful in the treatment of patients with specific tumors refractory to standard treatment and/or whose bone marrow status precluded the use of conventional chemotherapy. The final role of bleomycin in cancer chemotherapy awaits the results of controlled prospective clinical trials.

A Topoisomerase IIß-Mediated dsDNA Break Required for Regulated Transcription

2006-06-22

Bong‐Gun Ju , Victoria V. Lunyak , Valentina Perissi +4 more

Multiple enzymatic activities are required for transcriptional initiation. The enzyme DNA topoisomerase II associates with gene promoter regions and can generate breaks in double-stranded DNA (dsDNA). Therefore, it is of … Multiple enzymatic activities are required for transcriptional initiation. The enzyme DNA topoisomerase II associates with gene promoter regions and can generate breaks in double-stranded DNA (dsDNA). Therefore, it is of interest to know whether this enzyme is critical for regulated gene activation. We report that the signal-dependent activation of gene transcription by nuclear receptors and other classes of DNA binding transcription factors, including activating protein 1, requires DNA topoisomerase IIbeta-dependent, transient, site-specific dsDNA break formation. Subsequent to the break, poly(adenosine diphosphate-ribose) polymerase-1 enzymatic activity is induced, which is required for a nucleosome-specific histone H1-high-mobility group B exchange event and for local changes of chromatin architecture. Our data mechanistically link DNA topoisomerase IIbeta-dependent dsDNA breaks and the components of the DNA damage and repair machinery in regulated gene transcription.

Apoptosis induced by anticancer drugs

1992-09-01

John A. Hickman

Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan

2004-03-09

Federico Innocenti , Samir D. Undevia , Lalitha Iyer +7 more

Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence … Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation.Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped.The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51).UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.

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Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note.

1989-11-01

Scott H. Kaufmann

Treatment of human HL-60 or KG1A leukemia cells with the topoisomerase II inhibitor etoposide resulted in extensive DNA degradation. When DNA integrity was analyzed by agarose gel electrophoresis, a nucleosomal … Treatment of human HL-60 or KG1A leukemia cells with the topoisomerase II inhibitor etoposide resulted in extensive DNA degradation. When DNA integrity was analyzed by agarose gel electrophoresis, a nucleosomal ladder became evident 1.5-2 h after addition of etoposide to cells, increased in intensity over 6 h, and persisted at 24 h. Six h after addition of the drug, 94 +/- 4% of the cells excluded trypan blue even though as much as 90% of the DNA had been degraded to oligosomal fragments. Exposure of cells to 10 micrograms/ml (17 microM) etoposide for as little as 45 min was sufficient to induce this DNA damage 4 h later. Preincubation with dinitrophenol abolished the effect of etoposide, suggesting that an energy-requiring step occurred prior to or during the endonucleolytic cleavage. In contrast, the effect of etoposide was not prevented by preincubation of HL-60 cells with the RNA synthesis inhibitor 5,6-dichloro-1-beta-ribofuranosylbenzimidazole or the protein synthesis inhibitors cycloheximide or puromycin. On the contrary, high concentrations of 5,6-dichloro-1-beta-ribofuranosylbenzimidazole, cycloheximide, or puromycin by themselves induced the same endonucleolytic cleavage, as did a variety of diverse cytotoxic agents, including camptothecin (0.1 microM), colcemid (0.1 microgram/ml), cis-platinum (20 microM), methotrexate (1 microM), and 1-beta-D-arabinofuranosylcytosine (3 microM). These results suggest that endonucleolytic DNA damage by a preexisting cellular enzyme occurs soon after treatment of HL-60 cells with any of a variety of cytotoxic agents. The observation that a variety of nuclear proteins [including poly(ADP-ribose) polymerase, lamin B, topoisomerase I, topoisomerase II, and histone H1] are degraded concomitant with the DNA fragmentation calls into question the selectivity of the degradative process for DNA. The implications of these results for (a) current theories which focus upon endonucleolytic damage of DNA as a critical early event during cell death, and (b) use of topoisomerase-directed drugs to map topoisomerase-binding sites in active chromatin are discussed.

Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen

1995-02-01

Michael R. Boyd , Kenneth D. Paull

Abstract During 1985–1990 the U.S. National Cancer Institute (NCI) phased out its murine leukemia P388 anticancer drug screening program and developed as the replacement a new in vitro primary screen … Abstract During 1985–1990 the U.S. National Cancer Institute (NCI) phased out its murine leukemia P388 anticancer drug screening program and developed as the replacement a new in vitro primary screen based upon a diverse panel of human tumor cell lines. For each substance tested, the screen generates a remarkably reproducible and characteristic profile of differential in vitro cellular sensitivity, or lack thereof, across the 60 different cell lines comprising the panel. Several investigational approaches to display, analysis, and interpretation of such profiles and databases, derived from the testing of tens of thousands of substances during the past 4–5 years since the NCI screen became fully operational, have been explored. A variety of useful, practical applications of the in vitro screen have become apparent. As these applications continue to evolve, they are proving to be complementary to diverse other anticancer screening and drug discovery strategies being developed or pursued elsewhere. Reviewed herein are some practical considerations and selected specific examples, particularly illustrating research applications of the NCI screen that may be more broadly applicable to the search for new anticancer drug development leads with novel profiles of antitumor activity and/or mechanisms of action. © 1995 Wiley‐Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.

Cellular roles of DNA topoisomerases: a molecular perspective

2002-06-01

James C. Wang

Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis.

1993-09-01

Scott H. Kaufmann , Serge Desnoyers , Yvonne Ottaviano +2 more

Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, the proteolytic cleavage of poly(ADP-ribose) … Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, the proteolytic cleavage of poly(ADP-ribose) polymerase (pADPRp) during the course of chemotherapy-induced apoptosis was examined. Treatment of HL-60 human leukemia cells with the topoisomerase II-directed anticancer agent etoposide resulted in morphological changes characteristic of apoptosis. Endonucleolytic degradation of DNA to generate nucleosomal fragments occurred simultaneously. Western blotting with epitope-specific monoclonal and polyclonal antibodies revealed that these characteristic apoptotic changes were accompanied by early, quantitative cleavage of the M(r) 116,000 pADPRp polypeptide to an M(r) approximately 25,000 fragment containing the amino-terminal DNA-binding domain of pADPRp and an M(r) approximately 85,000 fragment containing the automodification and catalytic domains. Activity blotting revealed that the M(r) approximately 85,000 fragment retained basal pADPRp activity but was not activated by exogenous nicked DNA. Similar cleavage of pADPRp was observed after exposure of HL-60 cells to a variety of chemotherapeutic agents including cis-diaminedichloroplatinum(II), colcemid, 1-beta-D-arabinofuranosylcytosine, and methotrexate; to gamma-irradiation; or to the protein synthesis inhibitors puromycin or cycloheximide. Similar changes were observed in MDA-MB-468 human breast cancer cells treated with trifluorothymidine or 5-fluoro-2'-deoxyuridine and in gamma-irradiated or glucocorticoid-treated rat thymocytes undergoing apoptosis. Treatment with several compounds (tosyl-L-lysine chloromethyl ketone, tosyl-L-phenylalanine chloromethyl ketone, N-ethylmaleimide, iodoacetamide) prevented both the proteolytic cleavage of pADPRp and the internucleosomal fragmentation of DNA. The results suggest that proteolytic cleavage of pADPRp, in addition to being an early marker of chemotherapy-induced apoptosis, might reflect more widespread proteolysis that is a critical biochemical event early during the process of physiological cell death.

DNA Topoisomerases: Structure, Function, and Mechanism

2001-06-01

James J. Champoux

▪ Abstract DNA topoisomerases solve the topological problems associated with DNA replication, transcription, recombination, and chromatin remodeling by introducing temporary single- or double-strand breaks in the DNA. In addition, these … ▪ Abstract DNA topoisomerases solve the topological problems associated with DNA replication, transcription, recombination, and chromatin remodeling by introducing temporary single- or double-strand breaks in the DNA. In addition, these enzymes fine-tune the steady-state level of DNA supercoiling both to facilitate protein interactions with the DNA and to prevent excessive supercoiling that is deleterious. In recent years, the crystal structures of a number of topoisomerase fragments, representing nearly all the known classes of enzymes, have been solved. These structures provide remarkable insights into the mechanisms of these enzymes and complement previous conclusions based on biochemical analyses. Surprisingly, despite little or no sequence homology, both type IA and type IIA topoisomerases from prokaryotes and the type IIA enzymes from eukaryotes share structural folds that appear to reflect functional motifs within critical regions of the enzymes. The type IB enzymes are structurally distinct from all other known topoisomerases but are similar to a class of enzymes referred to as tyrosine recombinases. The structural themes common to all topoisomerases include hinged clamps that open and close to bind DNA, the presence of DNA binding cavities for temporary storage of DNA segments, and the coupling of protein conformational changes to DNA rotation or DNA movement. For the type II topoisomerases, the binding and hydrolysis of ATP further modulate conformational changes in the enzymes to effect changes in DNA topology.

DNA gyrase, topoisomerase IV, and the 4-quinolones

1997-09-01

Karl Drlica , Xilin Zhao

For many years, DNA gyrase was thought to be responsible both for unlinking replicated daughter chromosomes and for controlling negative superhelical tension in bacterial DNA. However, in 1990 a homolog … For many years, DNA gyrase was thought to be responsible both for unlinking replicated daughter chromosomes and for controlling negative superhelical tension in bacterial DNA. However, in 1990 a homolog of gyrase, topoisomerase IV, that had a potent decatenating activity was discovered. It is now clear that topoisomerase IV, rather than gyrase, is responsible for decatenation of interlinked chromosomes. Moreover, topoisomerase IV is a target of the 4-quinolones, antibacterial agents that had previously been thought to target only gyrase. The key event in quinolone action is reversible trapping of gyrase-DNA and topoisomerase IV-DNA complexes. Complex formation with gyrase is followed by a rapid, reversible inhibition of DNA synthesis, cessation of growth, and induction of the SOS response. At higher drug concentrations, cell death occurs as double-strand DNA breaks are released from trapped gyrase and/or topoisomerase IV complexes. Repair of quinolone-induced DNA damage occurs largely via recombination pathways. In many gram-negative bacteria, resistance to moderate levels of quinolone arises from mutation of the gyrase A protein and resistance to high levels of quinolone arises from mutation of a second gyrase and/or topoisomerase IV site. For some gram-positive bacteria, the situation is reversed: primary resistance occurs through changes in topoisomerase IV while gyrase changes give additional resistance. Gyrase is also trapped on DNA by lethal gene products of certain large, low-copy-number plasmids. Thus, quinolone-topoisomerase biology is providing a model for understanding aspects of host-parasite interactions and providing ways to investigate manipulation of the bacterial chromosome by topoisomerases.

Topoisomerase I inhibitors: camptothecins and beyond

2006-09-22

Yves Pommier

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Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis.

2000-12-15

Yukio Ando , Hideo Saka , Maki Ando +7 more

Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of … Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of the UGT1A1 would affect an interindividual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. In this case-control study, retrospective review of clinical records and determination of UGT1A1 polymorphisms were performed to investigate whether a patient with the variant UGT1A1 genotypes would be at higher risk for severe toxicity by irinotecan. All patients previously received irinotecan against cancer in university hospitals, cancer centers, or large urban hospitals in Japan. We identified 26 patients who experienced severe toxicity and 92 patients who did not. The relationship was studied between the multiple variant genotypes (UGT1A1*28 in the promoter and UGT1A1*6, UGT1A1*27, UGT1A1*29, and UGT1A1*7 in the coding region) and the severe toxicity of grade 4 leukopenia (< or =0.9 x 10(9)/liter) and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26 patients with the severe toxicity, the genotypes of UGT1A1*28 were homozygous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 10 (11%) heterozygous were found among the 92 patients without the severe toxicity. Multivariate analysis suggested that the genotype either heterozygous or homozygous for UGT1A1*28 would be a significant risk factor for severe toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence interval, 2.52-22.3). All 3 patients heterozygous for UGT1A1*27 encountered severe toxicity. No statistical association of UGT1A1*6 with the occurrence of severe toxicity was observed. None had UGT1A1*29 or UGT1A1*7. We suggest that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients. This research warrants a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 polymorphisms prior tb irinotecan chemotherapy.

Quinolone resistance-determining region in the DNA gyrase gyrB gene of Escherichia coli

1991-08-01

Hisahiro Yoshida , M Bogaki , Mami Nakamura +2 more

Thirteen spontaneous quinolone-resistant gyrB mutants of Escherichia coli KL16, including two that were examined previously, were divided into two types according to their quinolone resistance patterns. Type 1 mutants were … Thirteen spontaneous quinolone-resistant gyrB mutants of Escherichia coli KL16, including two that were examined previously, were divided into two types according to their quinolone resistance patterns. Type 1 mutants were resistant to all the quinolones tested, while type 2 mutants were resistant to acidic quinolones and were hypersusceptible to amphoteric quinolones. Nucleotide sequence analysis disclosed that all nine type 1 mutants had a point mutation from aspartic acid to asparagine at amino acid 426 and that all four type 2 mutants had a point mutation from lysine to glutamic acid at amino acid 447.

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Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin.

1988-04-01

Yaw Huei Hsiang , Leroy F. Liu

Camptothecin, a plant alkaloid with antitumor activity, has been shown to be a potent inhibitor of nucleic acid synthesis and a strong inducer of DNA strand breaks in mammalian cells. … Camptothecin, a plant alkaloid with antitumor activity, has been shown to be a potent inhibitor of nucleic acid synthesis and a strong inducer of DNA strand breaks in mammalian cells. Previous studies have shown that camptothecin inhibits purified mammalian DNA topoisomerase I by trapping a reversible enzyme-DNA "cleavable complex" (Hsiang et al., J. Biol. Chem., 260: 14873-14878, 1985). Our present studies, using L1210 cells and SV40-infected monkey cells, have shown that camptothecin-induced strand breaks are protein linked. The linked protein is most likely DNA topoisomerase I as revealed by immunoblot analysis, using antibodies against purified mammalian DNA topoisomerase I. Brief heating of camptothecin-treated cells to 65 degrees C resulted in a rapid reduction of the number of protein-linked DNA breaks. Reversal of the camptothecin-induced topoisomerase I-DNA complex by heat was also observed in an in vitro system by using purified mammalian DNA topoisomerase I. Our results suggest that camptothecin interferes with DNA topoisomerase I both in cultured mammalian cells and in the purified system by trapping a reversible enzyme-DNA cleavable complex.

Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003-10-20

Zahid H. Siddik

DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1

2016-03-30

Yusuke Ogitani , Tetsuo Aida , Katsunobu Hagihara +7 more

An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed.In vitro and in vivo … An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed.In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.DS-8201a exhibited a HER2 expression-dependent cell growth-inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Binding activity to HER2 and ADCC activity of DS-8201a were comparable with unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a as being well tolerated in humans. DS-8201a was effective in a T-DM1-insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated antitumor efficacy against several breast cancer PDX models with low HER2 expression.DS-8201a exhibited a potent antitumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1-insensitive HER2-positive cancers and low HER2-expressing cancers. Clin Cancer Res; 22(20); 5097-108. ©2016 AACR.

Roles of eukaryotic topoisomerases in transcription, replication and genomic stability

2016-09-21

Yves Pommier , Yilun Sun , Shar-yin N. Huang +1 more

The Different Mechanisms of Cancer Drug Resistance: A Brief Review

2017-09-25

Behzad Mansoori , Ali Mohammadi , Sadaf Davudian +2 more

Anticancer drugs resistance is a complex process that arises from altering in the drug targets.Advances in the DNA microarray, proteomics technology and the development of targeted therapies provide the new … Anticancer drugs resistance is a complex process that arises from altering in the drug targets.Advances in the DNA microarray, proteomics technology and the development of targeted therapies provide the new strategies to overcome the drug resistance.Although a design of the new chemotherapy agents is growing quickly, effective chemotherapy agent has not been discovered against the advanced stage of cancer (such as invasion and metastasis).The cancer cell resistance against the anticancer agents can be due to many factors such as the individual's genetic differences, especially in tumoral somatic cells.Also, the cancer drug resistance is acquired, the drug resistance can be occurred by different mechanisms, including multi-drug resistance, cell death inhibiting (apoptosis suppression), altering in the drug metabolism, epigenetic and drug targets, enhancing DNA repair and gene amplification.In this review, we outlined the mechanisms of cancer drug resistance and in following, the treatment failures by common chemotherapy agents in the different type of cancers.

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FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics.

1987-01-01

Toru Kino , Hiroshi Hatanaka , MICHISANE HASHIMOTO +6 more

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Editorial: Adverse Effects of Cancer Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae?

2018-03-22

Kulmira Nurgali , R. Thomas Jagoe , Raquel Abalo

EDITORIAL article Front. Pharmacol., 22 March 2018Sec. Pharmacology of Anti-Cancer Drugs Volume 9 - 2018 | https://doi.org/10.3389/fphar.2018.00245 EDITORIAL article Front. Pharmacol., 22 March 2018Sec. Pharmacology of Anti-Cancer Drugs Volume 9 - 2018 | https://doi.org/10.3389/fphar.2018.00245

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Biochemical Modulation of Cisplatin Mechanisms of Action: Enhancement of Antitumor Activity and Circumvention of Drug Resistance

2003-02-22

Miguel A. Fuertes , Carlos Alonso‐Moreno , José M. Pérez

ADVERTISEMENT RETURN TO ISSUEArticleNEXTBiochemical Modulation of Cisplatin Mechanisms of Action: Enhancement of Antitumor Activity and Circumvention of Drug ResistanceMiguel A. Fuertes, Carlos Alonso, and José. M. PérezView Author Information Centro … ADVERTISEMENT RETURN TO ISSUEArticleNEXTBiochemical Modulation of Cisplatin Mechanisms of Action: Enhancement of Antitumor Activity and Circumvention of Drug ResistanceMiguel A. Fuertes, Carlos Alonso, and José. M. PérezView Author Information Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), and Departamento de Química Inorgánica, Facultad de Ciencias, Universidad Autónoma de Madrid 28049-Madrid, Spain Cite this: Chem. Rev. 2003, 103, 3, 645–662Publication Date (Web):February 22, 2003Publication History Received10 October 2002Published online22 February 2003Published inissue 1 March 2003https://pubs.acs.org/doi/10.1021/cr020010dhttps://doi.org/10.1021/cr020010dresearch-articleACS PublicationsCopyright © 2003 American Chemical SocietyRequest reuse permissionsArticle Views5938Altmetric-Citations741LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Antineoplastic agents,Apoptosis,Cells,Genetics,Peptides and proteins Get e-Alerts

Mechanisms of Multidrug Resistance in Cancer Chemotherapy

2020-05-02

Karol Bukowski , Mateusz Kciuk , Renata Kontek

Cancer is one of the main causes of death worldwide. Despite the significant development of methods of cancer healing during the past decades, chemotherapy still remains the main method for … Cancer is one of the main causes of death worldwide. Despite the significant development of methods of cancer healing during the past decades, chemotherapy still remains the main method for cancer treatment. Depending on the mechanism of action, commonly used chemotherapeutic agents can be divided into several classes (antimetabolites, alkylating agents, mitotic spindle inhibitors, topoisomerase inhibitors, and others). Multidrug resistance (MDR) is responsible for over 90% of deaths in cancer patients receiving traditional chemotherapeutics or novel targeted drugs. The mechanisms of MDR include elevated metabolism of xenobiotics, enhanced efflux of drugs, growth factors, increased DNA repair capacity, and genetic factors (gene mutations, amplifications, and epigenetic alterations). Rapidly increasing numbers of biomedical studies are focused on designing chemotherapeutics that are able to evade or reverse MDR. The aim of this review is not only to demonstrate the latest data on the mechanisms of cellular resistance to anticancer agents currently used in clinical treatment but also to present the mechanisms of action of novel potential antitumor drugs which have been designed to overcome these resistance mechanisms. Better understanding of the mechanisms of MDR and targets of novel chemotherapy agents should provide guidance for future research concerning new effective strategies in cancer treatment.

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DNA gyrase, topoisomerase IV, and the 4-quinolones.

1997-01-01

Karl Drlica , Xilin Zhao

DNA TOPOISOMERASES

1996-06-01

J C Wang

The various problems of disentangling DNA strands or duplexes in a cell are all rooted in the double-helical structure of DNA. Three distinct subfamilies of enzymes, known as the DNA … The various problems of disentangling DNA strands or duplexes in a cell are all rooted in the double-helical structure of DNA. Three distinct subfamilies of enzymes, known as the DNA topoisomerases, have evolved to solve these problems. This review focuses on work in the past decade on the mechanisms and cellular functions of these enzymes. Newly discovered members and recent biochemical and structural results are reviewed, and mechanistic implications of these results are summarized. The primary cellular functions of these enzymes, including their roles in replication, transcription, chromosome condensation, and the maintenance of genome stability, are then discussed. The review ends with a summary of the regulation of the cellular levels of these enzymes and a discussion of their association with other cellular proteins.

6-Methoxydihydroavicine is a benzophenanthridine alkaloid with anti-leukemia activity

2025-06-24

Yingying Yang , Paul A. Spagnuolo | Frontiers in Pharmacology

Background Acute myeloid leukemia (AML) is an aggressive hematological malignancy with limited therapeutic options. Despite recent advances in targeted therapies, patients are still faced with poor survival outcomes. Thus, development … Background Acute myeloid leukemia (AML) is an aggressive hematological malignancy with limited therapeutic options. Despite recent advances in targeted therapies, patients are still faced with poor survival outcomes. Thus, development of novel therapeutic agents with broad efficacy remains an urgent need. Methods We conducted a natural compound library screen and identified 6-methoxydihydroavicine, a plant-derived benzophenanthridine alkaloid (BPA) derived from the genus of Macleaya - a perennial herb found in China, North America and Europe - as a potent compound that reduced AML cell viability. We evaluated its cytotoxicity in multiple AML cell lines and investigated its underlying mechanism of action using assays that probed mitochondrial function, and reactive oxygen species (ROS) production. Results 6-methoxydihydroavicine significantly reduced cell viability and induced caspase-mediated cell death in AML cell lines in a dose-dependent manner. Mechanistically, 6-methoxydihydroavicine triggered accumulation of mitochondrial ROS and disrupted electron transport chain (ETC) function. Conclusion Our findings demonstrate that 6-methoxydihydroavicine exerts strong cytotoxic effects against AML cells through mitochondrial dysfunction and ROS-mediated apoptosis. As a natural, plant-derived compound with distinct anti-AML properties, 6-methoxydihydroavicine represents a promising candidate for further development as a therapeutic agent for AML.

Topoisomerase I Inhibition in ETV4‐overexpressed Non‐Small Cell Lung Cancer Promotes Replication and Transcription Mediated R‐Loop Accumulation and DNA Damage

2025-06-23

Jiaxi Zhang , Yan Wang , Shan‐Hu Cao +7 more | Advanced Science

Coordinating transcription and replication via transcription factors (TFs) is a conserved mechanism in higher eukaryotes. The role of TFs in regulating these processes in cancers remains unclear. Here, it is … Coordinating transcription and replication via transcription factors (TFs) is a conserved mechanism in higher eukaryotes. The role of TFs in regulating these processes in cancers remains unclear. Here, it is shown that oncogenetic ETS transcription factor ETV4 controls DNA replication through both transcriptional and non-transcriptional mechanisms in non-small cell lung cancer (NSCLC). ETV4 localizes to specific DNA replication origins and interacts with the origin recognition complex subunits ORC1 and ORC6 during the G1/S phase, facilitating origin formation. Using quantitative in situ analysis of protein interactions at DNA replication forks (SIRF) assays, it is shown that ETV4 transiently localizes to replication forks in the S phase. It interacts with replicative helicase MCM2 N-terminal, histone H3, and histone-chaperone FACT and is involved in histone processing during replication. Additionally, ETV4 transcriptionally regulates key replisome genes MCM2, MCM4, MCM5, MCM10, and ORC1, influencing their expression and recruitment to chromatin. Due to its binding at the origin-promoter locus like the MCM4 gene, ETV4 overexpression increases R-loop formation, DNA damage, and cell death under external replication stress induced by topoisomerase I (TOP1) inhibitor. These findings highlight the dual role of ETV4 in replication and transcription and suggest that targeting TOP1 could be a synthetic-lethal approach in ETV4-overexpressed lung cancer.

Pharmacokinetics of Binimetinib in Participants with Hepatic Impairment

2025-06-23

Joseph Piscitelli , E. G. Hahn , Lance Wollenberg +3 more | Clinical Pharmacokinetics

Binimetinib is approved for multiple indications at a therapeutic dose of 45 mg twice a day (BID), in combination with encorafenib. A clinical hepatic impairment (HI) study was designed to … Binimetinib is approved for multiple indications at a therapeutic dose of 45 mg twice a day (BID), in combination with encorafenib. A clinical hepatic impairment (HI) study was designed to evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of binimetinib in participants with mild, moderate, and severe HI compared with demographically matched healthy participants with respect to age, gender, and body weight. Participants were enrolled according to National Cancer Institute (NCI) classification criteria for hepatic function based on their total bilirubin and aspartate aminotransferase levels at screening. Participants enrolled into Group 1 (normal hepatic function) were matched to participants enrolled into Groups 2, 3, and 4 (mild, moderate, and severe HI, respectively) with respect to age, gender, and body weight. Dose-normalized PK parameters were evaluated because of a difference in doses for the severe HI group compared to the other groups, with the dose reduction due to the increased exposures observed in the moderate HI group. Among 27 PK evaluable participants, changes in binimetinib dose-normalized PK parameters Cmax/D and AUCinf/D were minimal in participants with mild HI compared to the normal hepatic function group. Both the moderate and severe HI groups had significant changes as AUCinf/D increased by 81% and 111%, respectively, compared to the normal hepatic function group. Unbound AUClast/D for the moderate and severe HI groups increased by 280% and 248% compared to the normal hepatic function group, respectively. Based on these findings on total and unbound exposures, dose reductions are recommended for binimetinib in cancer patients with moderate and severe HI. ClinicalTrials.gov NCT02050815, registered 29 January 2014.

Targeting Topoisomerase I and DNA with LCS1269 Drives Glioblastoma Cell Death Despite ATM/Chk1/BRCA1/RAD51 Signaling Pathway Activation

2025-06-23

Nikolay Kalitin , Ekaterina Savchenko , Nadezhda Samoylenkova +4 more | International Journal of Molecular Sciences

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The success of modern multimodal standards approved in anti-glioblastoma therapy remains limited. Consequently, new therapeutics are urgently needed. In … Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The success of modern multimodal standards approved in anti-glioblastoma therapy remains limited. Consequently, new therapeutics are urgently needed. In this study, utilizing ex vivo, in silico, and in vitro approaches, we investigated the LCS1269 effects on two potential targets, DNA and Top I. We also elucidated the influence of LCS1269 on signaling pathways and GBM cell viability. Based on our docking data and competition studies results, we demonstrated that LCS1269 may bind to DNA, demonstrating selectivity toward AT-rich regions. We also showed that LCS1269 could dock both Top I/DNA binary complex and Top I active sites. LCS1269 caused Top I dysfunction and downregulated the expression of Top I. Moreover, the LCS1269 treatment of GBM cells facilitated DNA damage and the activation of the ATM/Chk1/BRCA1/Rad51 pathway. Meanwhile, DNA damage response induction and ATM/Chk1/BRCA1/Rad51 pathway activation were insufficient to prevent GBM cell death triggered by LCS1269 treatment. Our work shows that DNA and Top I are promising molecular targets of LCS1269, thus providing insight on several novel mechanisms of its anti-tumor activity. Nonetheless, we did not perform a biophysical validation of the LCS1269–DNA interaction, which is a limitation of our study.

Structural Innovations in Vancomycin: Overcoming Resistance and Expanding the Antibacterial Spectrum

2025-06-23

Ricardo Cartes‐Velásquez , Felipe Morales-León , Franco Valdebenito-Maturana +3 more | Organics

Vancomycin, a cornerstone antibiotic against severe Gram-positive infections, is increasingly challenged by resistance in Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin Enterococcus spp. (VRE), necessitating the development of novel therapeutic strategies. … Vancomycin, a cornerstone antibiotic against severe Gram-positive infections, is increasingly challenged by resistance in Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin Enterococcus spp. (VRE), necessitating the development of novel therapeutic strategies. This review examines how structural modifications to vancomycin can enhance its antibacterial activity and explores the critical role of computational approaches in designing the next generation of analogs. By analyzing the existing literature, we highlight how strategic alterations, such as the introduction of lipophilic side chains, substitutions on the sugar moieties, and modifications to the aglycone core, have yielded derivatives with improved antibacterial potency. Notably, certain analogs (e.g., Vanc-83, Dipi-Van-Zn) have demonstrated expanded activity against Gram-negative bacteria and exhibited enhanced pharmacokinetic profiles, including prolonged half-lives and improved tissue penetration, crucial for effective treatment. Semisynthetic glycopeptides like telavancin, dalbavancin, and oritavancin exemplify successful translation of structural modifications, offering sustained plasma concentrations and simplified dosing regimens that improve patient compliance. Complementing these experimental efforts, computational methods, including molecular docking and molecular dynamics simulations, provide valuable insights into drug–target interactions, guiding the rational design of more effective analogs. Furthermore, physiologically based pharmacokinetic modeling aids in predicting the in vivo behavior and optimizing the pharmacokinetic properties of these novel compounds. This review highlights a critical path forward in the fight against multidrug-resistant infections. By meticulously examining the previously carried out structural refinement of vancomycin, guided by computational predictions and validated through rigorous experimental testing, we underscore its immense potential.

Exploring Carboxamide Derivatives as Promising Anticancer Agents: Design, In Vitro Evaluation, and Mechanistic Insights

2025-06-19

Manal Al-Najdawi , Maysaa M. Saleh , Dima A. Sabbah +7 more | International Journal of Molecular Sciences

Carboxamide derivatives are a promising class of compounds in anticancer drug discovery, owing to their ability to interact with multiple oncogenic targets and their favorable pharmacological profiles. In this study, … Carboxamide derivatives are a promising class of compounds in anticancer drug discovery, owing to their ability to interact with multiple oncogenic targets and their favorable pharmacological profiles. In this study, we report the design, synthesis, and biological evaluation of a series of N-substituted 1H-indole-2-carboxamides as potential anticancer agents. The synthesized compounds were assessed for antiproliferative activity using the MTT assay against MCF-7 (breast cancer), K-562 (leukemia), and HCT-116 (colon cancer) cell lines, with normal human dermal fibroblasts included as a non-cancerous control. Several compounds demonstrated notable cytotoxicity and selectivity. Compounds 12, 14, and 4 exhibited potent activity against K-562 cells, with IC50 values of 0.33 µM, 0.61 µM, and 0.61 µM, respectively. Compound 10 showed the most significant activity against HCT-116 cells (IC50 = 1.01 µM) with a high selectivity index (SI = 99.4). Moderate cytotoxicity was observed against MCF-7 cells. To elucidate the mechanism of action, molecular docking and induced-fit docking studies were conducted against key cancer-related targets, including topoisomerase-DNA (PDB ID: 5ZRF), PI3Kα (4L23), and EGFR (3W32), revealing favorable binding interactions. Additionally, principal component analysis of molecular descriptors indicated that the compounds possess promising drug-like and lead-like properties, particularly compound 10. Overall, this study highlights N-substituted indole-2-carboxamides as promising scaffolds for further optimization. The integration of synthetic chemistry, biological assays, and computational modeling provides a robust foundation for the continued development of these compounds as potential anticancer agents.

Targeting Artemis Sensitizes B Cells to Topoisomerase 2 Poisons by Disrupting DNA-PKcs-Dependent Repair

2025-06-19

Nicholas R. Pannunzio , Melissa L. Folkerts , Christy Hom +7 more | Research Square (Research Square)

Topoisomerase 2 (Top2) poisons are widely used in cancer therapy but are associated with toxicity and secondary malignancies. Removing Top2 adducts requires endonuclease activity and repair by non-homologous end joining … Topoisomerase 2 (Top2) poisons are widely used in cancer therapy but are associated with toxicity and secondary malignancies. Removing Top2 adducts requires endonuclease activity and repair by non-homologous end joining (NHEJ). We show that the NHEJ enzyme Artemis is a promising target for co-treatment with Top2 poisons. Inhibition of the Artemis activator, DNA-PKcs, with peposertib (M3814) sensitizes B cells to Top2 poisons while ATM or ATR inhibition does not. Interestingly, while M3814 treatment blocks Artemis endonuclease activity, Artemis phosphorylation is still detectible and is only affected upon inhibiting ATM, suggestive of an additional role for Artemis in DNA damage response signaling. Additionally, Artemis loss results in a significant accumulation of Top2 DNA adducts following treatment, indicating Artemis may act outside its canonical role in NHEJ to reduce adduct burden. Clinical data demonstrates that high Artemis expression correlates with poor survival in several cancers, and we demonstrate that Artemis function is critical for survival following combination drug treatment. These insights can be leveraged to unlock new avenues for the treatment of aggressive cancers by enhancing the cytotoxicity of agents through blockade of DNA break repair.

Total Synthesis and Biological Evaluation of 22-Hydroxyacuminatine and the Related Natural Products Norketoyobyrine and Naucleficine

2025-06-19

Shohta Mizuno , Takashi Nishiyama , Hana Bessho +7 more | Molecules

Aromathecin compounds-which contain the same indolizine core structure as camptothecin-like compounds-are expected to show anticancer activity. Among them, 22-hydroxyacuminatine-which has a substituent on the E-ring of the pentacyclic scaffold-exhibits topoisomerase … Aromathecin compounds-which contain the same indolizine core structure as camptothecin-like compounds-are expected to show anticancer activity. Among them, 22-hydroxyacuminatine-which has a substituent on the E-ring of the pentacyclic scaffold-exhibits topoisomerase 1 inhibitory activity; therefore, the development of efficient methods for its synthesis has been actively pursued. Herein, we report a versatile synthetic methodology for introducing various substituents on the E-ring, leading to the total synthesis of 22-hydroxyacuminatine as a model compound of the aromathecin family. The synthesis comprises the following key steps: the synthesis of an isoquinoline N-oxide via the thermal cyclization of 2-alkynylbenzaldehyde oxime, the subsequent Reissert-Henze-type reaction to yield an isoquinolone, and the construction of the indolizine moiety (CD-ring) through C-N bond formation via the Mitsunobu reaction. Consequently, a pentacyclic benz[6,7]indolizino[1,2-b]quinolin-11(13H)-one framework is obtained. Using this methodology, the total synthesis of the natural products norketoyobyrine and naucleficine and an intermediate of the latter, which are indoloquinolizidine-type alkaloids, was achieved, and their antiproliferative activity against HCT-116 human colon cancer cells and HepG2 human liver cancer cells was assessed. Naucleficine and its intermediate exhibited moderate antiproliferative activity against HCT-116 cells, with IC50 values of 55.58 and 41.40 μM, respectively.

Taste Profile and Relative Bioavailability of Tovorafenib Powder for Oral Suspension and Food Effect of the Tovorafenib Tablet in Healthy Participants

2025-06-19

Yang Zhang , Mike Preigh , Jing Wang +4 more | Clinical Pharmacology in Drug Development

Abstract A pediatric‐friendly powder for oral suspension (PfOS) of tovorafenib, a type II RAF inhibitor, was developed for patients with difficulty swallowing tablets. This open‐label, randomized, phase 1 study (QSC205140) … Abstract A pediatric‐friendly powder for oral suspension (PfOS) of tovorafenib, a type II RAF inhibitor, was developed for patients with difficulty swallowing tablets. This open‐label, randomized, phase 1 study (QSC205140) evaluated the taste/palatability of PfOS formulations (n = 12), the relative bioavailability of the PfOS versus tablet formulation, and the food effect on tablets (n = 12) in healthy participants. Tovorafenib was initially administered at 300 mg and reduced to 100 mg due to musculoskeletal adverse events (AEs). The addition of sweetener and/or flavoring improved taste/palatability. Geometric mean ratios (90% confidence interval) of dose‐corrected peak plasma drug concentration (C max /D) and area under the plasma concentration–time curve from time zero to the last measurable concentration (AUC 0‐last /D) between the PfOS and tablet formulations were 96% (83%‐111%) and 104% (95%‐115%), respectively. Compared with fasted administration, administration of the tablet with food resulted in a 2‐3.5‐hours delay in time to C max, and a 20% reduction in C max /D with no change in AUC 0‐last /D. Four severe and 7 moderate AEs occurred with 300 mg of tovorafenib. All remaining AEs, reported with both 100 mg and 300 mg, were mild. These data suggest that tovorafenib PfOS and tablet formulations are comparable, and that the tablet can be administered with or without food.

1,8-naphthalimide-based DNA intercalators and anticancer agents: a systematic review

2025-06-18

Aeyaz Ahmad Bhat , Amel Gacem , Maytham T. Qasim +3 more | Molecular Diversity

Deuterium substitution at the intolerable site as a strategy to mitigate the toxicity of camptothecin derivatives

2025-06-17

Xianqiang Yu , Ziyu Sun , Jing Liu +6 more | European Journal of Medicinal Chemistry

Engineering an advanced multicomponent pentacyclic triterpenoid nanoplatform for synergistic co-delivery of cyclin-dependent kinase 4/6 inhibitors to enhance cancer chemoimmunotherapy

2025-06-17

Conglei Zhou , Yuqing Lian , Jianjun Cheng +3 more | Journal of Colloid and Interface Science

Elacridar Inhibits BCRP Protein Activity in 2D and 3D Cell Culture Models of Ovarian Cancer and Re-Sensitizes Cells to Cytotoxic Drugs

2025-06-17

Piotr Stasiak , Justyna Sopel , Artur Płóciennik +6 more | International Journal of Molecular Sciences

Chemotherapy resistance is a major obstacle in the treatment of ovarian cancer, often resulting in disease recurrence and poor prognosis for patients. A key contributor to this resistance is the … Chemotherapy resistance is a major obstacle in the treatment of ovarian cancer, often resulting in disease recurrence and poor prognosis for patients. A key contributor to this resistance is the overexpression of ATP-binding cassette (ABC) transporters, including breast cancer resistance protein (BCRP/ABCG2), which actively effluxes chemotherapeutic agents such as topotecan (TOP) or mitoxantrone (MIT), limiting their intracellular accumulation and efficacy. This study investigated the potential of elacridar (GG918), a potent dual P-gp and BCRP inhibitor, to overcome drug resistance in ovarian cancer cell lines. Both TOP-sensitive and TOP-resistant ovarian cancer cells were grown in two-dimensional (2D) monolayers and three-dimensional (3D) spheroid models to better mimic the tumor microenvironment. The expression of the ABCG2 gene was quantified via qPCR and BCRP protein levels were assessed by western blotting and immunofluorescence. Drug response was evaluated using MTT viability assays, while BCRP transporter activity was examined using flow cytometry and microscopic assessment of the intracellular retention of BCRP fluorescent substrates (Hoechst 33342 and MIT). In both 2D and 3D cultures, elacridar effectively inhibited BCRP function and significantly enhanced sensitivity to TOP. These findings suggest that elacridar can inhibit BCRP-mediated drug resistance in ovarian cancer cell models.

2,4-difluorophenyl(piperidin-4-yl) methanoneoxime derivatives as potent contenders to combat antibacterial resistance of MRSA: In-silico approach

2025-06-16

M. S. Punith , G. N. Ningaraju , S. Nanjundaswamy +6 more | Deleted Journal

Synthesis, Stability, and Biological Evaluation of Novel Ami-Noderivatives Incorporating the Aza-Acridine Scaffold

2025-06-16

Maria Karelou , Anthi Panara , Eleftheria Chatziorfanou +4 more | Molecules

Several new amino-substituted aza-acridine derivatives bearing one or two basic side chains have been designed and synthesized. Their anticancer activities were evaluated in vitro against two human cancer cell lines: … Several new amino-substituted aza-acridine derivatives bearing one or two basic side chains have been designed and synthesized. Their anticancer activities were evaluated in vitro against two human cancer cell lines: T24 (urothelial bladder carcinoma, malignancy grade III) and WM266-4 (metastatic melanoma). Some of the synthesized compounds induced significant antiproliferative effects, with WM266-4 cells appearing more susceptible than T24 cells. This apparent cell-type selectivity may reflect differences in the mutational profiles and molecular target landscapes between the two cancer models. A stability study under hydrolytic conditions, based on a validated method, indicated that the most active compounds were stable under aqueous conditions. Computational analysis further supported the stability of these analogs, providing insights into the structure-stability relationships of the synthesized compounds.

Discovery of Hybrids of Bisbibenzyl with Furoxan as Lysosomotropic Agents for the Treatment of Drug-Resistant Non-Small-Cell Lung Cancer

2025-06-15

Jiayu Sun , Suhua Qi , Qian Chen +7 more | European Journal of Medicinal Chemistry

Evaluation of the Antitumor and Antiproliferative Potential of Synthetic Peptides Derived from IsCT1, Associated with Cisplatin, in Squamous Cell Carcinoma of the Oral Cavity

2025-06-15

Laertty Garcia de Sousa Cabral , Cyntia Silva Oliveira , Vani Xavier Oliveira +3 more | Molecules

Head and neck squamous cell carcinoma (SCC), particularly in the oral cavity, is among the most prevalent and lethal forms of cancer globally. Current therapeutic strategies, predominantly involving cisplatin, face … Head and neck squamous cell carcinoma (SCC), particularly in the oral cavity, is among the most prevalent and lethal forms of cancer globally. Current therapeutic strategies, predominantly involving cisplatin, face challenges like chemoresistance and toxicity to normal cells, justifying the exploration of new approaches. This study evaluates the antitumor, antiproliferative, and immunomodulatory potential of a synthetic peptide derived from IsCT1 (Isalo scorpion cytotoxic peptide), named AC-AFPK-IsCT1, in combination with cisplatin in oral squamous cell carcinoma cellular models. Tumor and normal cells were treated with varying concentrations of cisplatin and peptide, and the cytotoxicity was measured through an MTT assay, while apoptosis and cell cycle alterations were assessed via flow cytometry. Interestingly, the combination of AC-AFPK-IsCT1 with cisplatin exhibited higher specificity for tumor cells, significantly reducing IC50 values compared to cisplatin used as a single agent. Moreover, the combination treatment induced pronounced S-phase cell cycle arrest and enhanced apoptotic activity, evidenced by the upregulation of caspase-3, caspase-8, and p53, while maintaining low toxicity in normal fibroblast cells. The peptide also modulated the mitochondrial membrane potential, further contributing to the activation of intrinsic apoptotic pathways. The data suggest that AC-AFPK-IsCT1 potentiates the antitumor effects of cisplatin by engaging both intrinsic and extrinsic apoptotic pathways while preserving normal cell viability. These findings underscore the potential of combining cisplatin with AC-AFPK-IsCT1 as a promising therapeutic strategy for improving the efficacy of chemotherapy in SCC, reducing systemic toxicity, and overcoming chemoresistance.

Abstract P3-09-22: Phenomenal: Efficacy and safety of liposomal irinotecan in patients with HER2-negative breast cancer and brain metastases

2025-06-13

Manuel Ruiz Borrego , D. Páez López-Bravo , Mireia Margelí Vila +7 more | Clinical Cancer Research

Abstract Background: Liposomal irinotecan (nal-IRI) is a novel formulation of irinotecan, a topoisomerase 1 inhibitor encapsulated in a liposome drug delivery system that has shown promising activity in patients (pts) … Abstract Background: Liposomal irinotecan (nal-IRI) is a novel formulation of irinotecan, a topoisomerase 1 inhibitor encapsulated in a liposome drug delivery system that has shown promising activity in patients (pts) with brain metastases (BMs). Phenomenal is a non-randomized phase IIa study evaluating the efficacy and safety of nal-IRI as single agent in HER2-negative (HER2[-]) breast cancer pts with previously untreated, stable or progressive BMs following local treatment. Methods: Phenomenal (NCT03328884) is an open-label, single-arm, multicenter, Simon two-stage phase IIa trial. Pts aged &gt;18 years with pretreated HER2[-] breast cancer with previously untreated, stable, or progressive BMs were enrolled. Pts received intravenous nal-IRI at 60 mg/m2 (if based on irinotecan hydrochloride trihydrate [salt base]) or 50 mg/m2 (if based on irinotecan anhydrous [free-base]) on day 1 of a 14-day cycle until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was intracranial objective response rate (IC-ORR) according to RANO-BM in pts with progressive BMs. It was locally confirmed at the next tumor assessment (after 6 weeks) or with a ≥65% volumetric reduction of IC lesions by blinded independent central review. Secondary endpoints included IC, extracranial (EC) and overall (IC + EC) ORR, progression-free survival (PFS), overall survival (OS), duration of response) and clinical benefit rate at 12 weeks according to RECIST v.1.1; and safety and tolerability as per NCI-CTCAE v.4.0. Primary analysis estimated the IC-ORR (H0≤5.0%; H1: IC-ORR ≥15.0%); 95% CI and p-value were calculated with the method of Jung and Koyama. Sample size was planned to attain an 80% power at a nominal α level of 0.05. Results: Between July 2017 and April 2024, 56 pts were allocated at 16 sites in Spain. Median age was 52 (range 32-83) years. A total of 3 and 51 pts had previously untreated and progressive BMs, respectively. Two patients had stable BMs. Twenty-seven pts (48.2%) had HR[+]/HER2[-] tumors and 29 pts (51.8%) had triple-negative breast cancer. The median number of previous lines of therapy for advanced disease was 3 (range, 1-8). At data cutoff (May 15th, 2024), with a median follow-up of 5.7 months (mo) (range, 0.4-56.5), 2 pts (3.6%) remained on therapy. The primary endpoint of the study was met with 10 pts out of 51 (19.6%; 95% CI 11.1-28.9) with progressive BMs achieving a confirmed IC-ORR (p&lt;0.001). IC-ORR in all pts was 19.6% (11/56 pts; 95% CI, 10.2–32.4). EC-ORR in pts with measurable extracranial disease was 2.7% (1/37 pts; 95% CI, 0.0-14.2) and overall (IC + EC) ORR in all pts was 5.4% (3/56 pts; 95% CI, 1.1–14.9). Median PFS was 1.5 mo (95% CI, 1.4-2.8). Median OS was 6.4 mo (95% CI, 4.3-10.8). The most common treatment emergent adverse events of any grade (G) were fatigue (55.4%; 7.1% G≥3) and headache (44.6%; 1.8% G≥3). There were no treatment-related deaths and no new safety issues were reported. Conclusions: Although the primary endpoint was achieved, nal-IRI showed limited antitumor activity in HER2[-] breast cancer pts with progressive BMs. These results do not support further evaluation of this treatment in this patient population. Citation Format: Manuel Ruiz Borrego, David Páez López-Bravo, Mireia Margelí Vila, José Manuel Pérez-García, María Fernández, Salvador Blanch Tormo, José Ángel García, Laura Lema, Isabel Garau, Patricia Cortez, Antonio Antón Torres, Emilio Alba Conejo, María Isabel Calvo, Neus Ferrer, María Isabel Blancas, Kepa Amillano, Marta Bertrán, Daniel Alcalá-López, Miguel Sampayo-Cordero, Javier Cortés, Antonio Llombart-Cussac. Phenomenal: Efficacy and safety of liposomal irinotecan in patients with HER2-negative breast cancer and brain metastases [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-09-22.

Synthesis, Characterization, and Anti-TB Application of Redox-Active Ethyl Carbazate-Derivatized Phenanthroline and Its Silver Complexes

2025-06-13

Ravallika Aluri , Aishwarya Natarajan , Jyothi Kumari +4 more | ACS Omega

IMPACT OF SUBSTITUENTS IN INDOLOBENZAZOCIN-8-ONE DERIVATIVES ON ANTICANCER ACTIVITY: INSIGHTS FROM MOLECULAR DOCKING AND ADMET PREDICTIONS

2025-06-07

Arthorn Loisruangsin , Sasiwadee Boonya‐udtayan , Weenawan Somphon | Asian Journal of Pharmaceutical and Clinical Research

Objectives: The objective of the study is to explore how substitutions modulate indolobenzazocin-8-one’s anticancer activity and advantages over taxanes using computational modeling. Methods: Molecular docking predicted binding affinities (Ei, kcaL/moL) … Objectives: The objective of the study is to explore how substitutions modulate indolobenzazocin-8-one’s anticancer activity and advantages over taxanes using computational modeling. Methods: Molecular docking predicted binding affinities (Ei, kcaL/moL) at β-tubulin’s colchicine site, while ADMET models evaluated physicochemical/ pharmacokinetic properties. Spearman’s rank correlation analysis was employed for assessing structural- activity relationships. Results: Cytotoxicity was primarily driven by cellular permeability, evidenced by a strong negative correlation between lipophilicity and potency (logD7.4-IC₅₀: ρ=−0.90, p=0.037), unlike the weak, non-significant association with binding affinity (Ei-IC₅₀: ρ=0.46, p=0.434). Methoxy substitution weakened binding (ΔEi increased up to 4.2 kcaL/moL) and had non-linear lipophilicity effects (mono-substitution: ΔlogD7.4=+0.031; di-substitution: ΔlogD7.4=−0.128). Hydroxy substitution enhanced affinity (ΔEi=−1.58 kcaL/moL) but compromised permeability (ΔlogD7.4=−0.095). The optimized lead compound balanced these trade-offs, showing high intestinal absorption (Caco-2 permeability (log cm/s)=−5.033) and low P-glycoprotein efflux risk (probability=0.117). Conclusion: Substitutions affect anticancer activity by altering both hydrophobicity and binding affinity. Unsubstituted indolobenzazocin-8-one demonstrated the most potent anticancer activity. In addition, its drug-like properties and bypass of P-gp-mediated resistance position it as a superior oral alternative to taxanes.

Huachansu injection enhances anti-colorectal cancer efficacy of irinotecan and alleviates its induced intestinal toxicity through upregulating UGT1A1-OATP1B3 expression in vitro and in vivo

2025-06-01

Bo Jiang , Zhaoyang Meng , Yujie Hu +6 more | Journal of Integrative Medicine

Design and Development of New Generation ALK Inhibitors Driven by Structure–Activity Relationship Studies of 2,4‐Diarylaminopyrimidine Derivatives

2025-06-01

Yakun Zhang , Jian‐Bo Tong , Minxia Luo +2 more | ChemistrySelect

Abstract Due to the oncogenic role of anaplastic lymphoma kinase (ALK) in various malignancies, particularly in non‐small cell lung cancer (NSCLC), lymphoma, and neuroblastoma, mutations or rearrangements of ALK frequently … Abstract Due to the oncogenic role of anaplastic lymphoma kinase (ALK) in various malignancies, particularly in non‐small cell lung cancer (NSCLC), lymphoma, and neuroblastoma, mutations or rearrangements of ALK frequently drive tumorigenesis and progression. Consequently, the development of new‐generation ALK inhibitors, particularly therapeutic strategies targeting ALK resistance mutations, has emerged as a critical focus in cancer drug research and development. This study established a robust Topomer CoMFA model, validated through both internal and external assessments, Y‐randomization testing, and validation with the extreme learning machine (ELM) model, to systematically analyze the structure–activity relationships (SAR) of a series of 52 derivatives, specifically designed as 2,4‐diarylaminopyrimidines, which exhibit significant inhibitory activity. Based on the optimal model, 24 novel compounds demonstrating ideal inhibitory activity were successfully designed, with three potential lead compounds identified through molecular docking. Subsequent investigations utilized DFT calculations, molecular dynamics simulations, principal component analysis, and binding free energy calculations to elucidate the binding modes and mechanisms of these compounds. Furthermore, ADMET predictions indicated promising pharmacological potential for these compounds. These results offer substantial theoretical support for the targeted treatment of ALK‐related tumors, while also laying the groundwork for future investigations into novel ALK inhibitors.

Functional identification of 10-hydroxygeraniol oxidoreductases related to camptothecin biosynthesis in Ophiorrhiza pumila

2025-06-01

Yongpeng Li , Qin Zhou , Xiaoxuan Fan +7 more | International Journal of Biological Macromolecules