Biochemistry, Genetics and Molecular Biology › Molecular Biology

Histone Deacetylase Inhibitors Research

Works Count: 28696

Wikipedia

Description

This cluster of papers explores the role of histone deacetylases (HDACs) in regulating cellular functions, gene expression, and epigenetic modifications. It covers the use of HDAC inhibitors in cancer therapy, their impact on neurodegenerative disorders, and their involvement in protein complexes and enzymatic activity.

Keywords

Histone Deacetylases; HDAC Inhibitors; Epigenetic Regulation; Cancer Therapy; Cellular Functions; Acetylation; Gene Expression; Neurodegenerative Disorders; Protein Complexes; Enzymatic Activity

Histone acetylation in chromatin structure and transcription

1997-09-01

Michael Grunstein

Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A.

1990-10-01

Minoru Yoshida , Masako Kijima , Motomu Akita +1 more

(R)-Trichostatin A (TSA) is a Streptomyces product which causes the induction of Friend cell differentiation and specific inhibition of the cell cycle of normal rat fibroblasts in the G1 and … (R)-Trichostatin A (TSA) is a Streptomyces product which causes the induction of Friend cell differentiation and specific inhibition of the cell cycle of normal rat fibroblasts in the G1 and G2 phases at the very low concentrations. We found that TSA caused an accumulation of acetylated histone species in a variety of mammalian cell lines. Pulse-labeling experiments indicated that TSA markedly prolonged the in vivo half-life of the labile acetyl groups on histones in mouse mammary gland tumor cells, FM3A. The partially purified histone deacetylase from wild-type FM3A cells was effectively inhibited by TSA in a noncompetitive manner with Ki = 3.4 nM. A newly isolated mutant cell line of FM3A resistant to TSA did not show the accumulation of the acetylated histones in the presence of a higher concentration of TSA. The histone deacetylase preparation from the mutant showed decreased sensitivity to TSA (Ki = 31 nM, noncompetitive). These results clearly indicate that TSA is a potent and specific inhibitor of the histone deacetylase and that the in vivo effect of TSA on cell proliferation and differentiation can be attributed to the inhibition of the enzyme.

Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation

2000-11-01

Timothy A. McKinsey , Chun‐Li Zhang , Jianrong Lu +1 more

Anticancer activities of histone deacetylase inhibitors

2006-09-01

Jessica E. Bolden , Melissa J. Peart , Ricky W. Johnstone

Histone-deacetylase inhibitors: novel drugs for the treatment of cancer

2002-04-01

Ricky W. Johnstone

Histone deacetylases and cancer

2007-08-13

Michele A. Glozak , Edward Seto

Acetylation and deacetylation of non-histone proteins

2005-11-12

Michele A. Glozak , Nilanjan Sengupta , Xiaohong Zhang +1 more

Nuclear Receptor Coactivator ACTR Is a Novel Histone Acetyltransferase and Forms a Multimeric Activation Complex with P/CAF and CBP/p300

1997-08-01

Hongwu Chen , Richard J. Lin , R. Louis Schiltz +6 more

View PDF Chat

Epigenetic therapy of cancer: past, present and future

2006-01-01

Christine B. Yoo , Peter A. Jones

Histone deacetylases and cancer: causes and therapies

2001-12-01

Paul A. Marks , Richard A. Rifkind , Victoria M. Richon +3 more

HDAC family: What are the cancer relevant targets?

2008-09-28

Olaf Witt , Hedwig E. Deubzer , Till Milde +1 more

Lysine Acetylation: Codified Crosstalk with Other Posttranslational Modifications

2008-08-01

Xiang‐Jiao Yang , Edward Seto

View PDF Chat

Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders

2014-08-18

Katrina J. Falkenberg , Ricky W. Johnstone

Decreased Histone Deacetylase Activity in Chronic Obstructive Pulmonary Disease

2005-05-11

Kazuhiro Ito , Misako Ito , W. Mark Elliott +7 more

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of … Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the reduction in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages.

View PDF Chat

Acetylation of Metabolic Enzymes Coordinates Carbon Source Utilization and Metabolic Flux

2010-02-18

Qijun Wang , Yakun Zhang , Chen Yang +7 more

Lysine acetylation regulates many eukaryotic cellular processes, but its function in prokaryotes is largely unknown. We demonstrated that central metabolism enzymes in Salmonella were acetylated extensively and differentially in response … Lysine acetylation regulates many eukaryotic cellular processes, but its function in prokaryotes is largely unknown. We demonstrated that central metabolism enzymes in Salmonella were acetylated extensively and differentially in response to different carbon sources, concomitantly with changes in cell growth and metabolic flux. The relative activities of key enzymes controlling the direction of glycolysis versus gluconeogenesis and the branching between citrate cycle and glyoxylate bypass were all regulated by acetylation. This modulation is mainly controlled by a pair of lysine acetyltransferase and deacetylase, whose expressions are coordinated with growth status. Reversible acetylation of metabolic enzymes ensure that cells respond environmental changes via promptly sensing cellular energy status and flexibly altering reaction rates or directions. It represents a metabolic regulatory mechanism conserved from bacteria to mammals.

View PDF Chat

HDAC6 is a microtubule-associated deacetylase

2002-05-01

Charlotte Hubbert , Amaris R. Guardiola , Rong Shao +6 more

Histone deacetylase inhibitors: molecular mechanisms of action

2007-08-13

Weisheng Xu , Raphael B. Parmigiani , P A Marks

NURD, a Novel Complex with Both ATP-Dependent Chromatin-Remodeling and Histone Deacetylase Activities

1998-12-01

Yutong Xue , Jiemin Wong , G. Tony Moreno +3 more

Epigenetic protein families: a new frontier for drug discovery

2012-04-13

C.H. Arrowsmith , C. Bountra , Paul V. Fish +2 more

View PDF Chat

Targeting cancer with small molecule kinase inhibitors

2008-12-19

Jianming Zhang , Priscilla L. Yang , Nathanael S. Gray

Regulation of Cellular Metabolism by Protein Lysine Acetylation

2010-02-18

Shimin Zhao , Wei Xu , Wenqing Jiang +7 more

Metabolic Regulation Through Acetylation Covalent modification of lysine residues in various proteins in the nucleus is a recognized mechanism for control of transcription. Now two papers suggest that acetylation may … Metabolic Regulation Through Acetylation Covalent modification of lysine residues in various proteins in the nucleus is a recognized mechanism for control of transcription. Now two papers suggest that acetylation may represent an important regulatory mechanism controlling the function of metabolic enzymes (see the Perspective by Norvell and McMahon ). Zhao et al. (p. 1000 ) found that a large proportion of enzymes in various metabolic pathways were acetylated in human liver cells. Acetylation regulated various enzymes by distinct mechanisms, directly activating some, inhibiting one, and controlling the stability of another. Control of metabolism by acetylation appears to be evolutionarily conserved: Wang et al. (p. 1004 ) found that the ability of the bacterium Salmonella entericum to optimize growth on distinct carbon sources required differential acetylation of key metabolic enzymes, thus controlling flux through metabolic pathways.

View PDF Chat

Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug

2007-01-01

Paul A. Marks , Ronald Breslow

HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention

2007-08-13

X-J Yang , Edward Seto

HDAC2 negatively regulates memory formation and synaptic plasticity

2009-05-01

Ji‐Song Guan , Stephen J. Haggarty , Emanuela Giacometti +7 more

The Deacetylase HDAC6 Regulates Aggresome Formation and Cell Viability in Response to Misfolded Protein Stress

2003-12-01

Yoshiharu Kawaguchi , Jeffrey J. Kovacs , Adam C. McLaurin +3 more

View PDF Chat

Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen

2001-09-01

Christopher J. Phiel , Fang Zhang , Eric Yi‐Hsiu Huang +3 more

Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We … Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC50 for HDAC1=0.4 mm). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.

View PDF Chat

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006-01-01

Saverio Minucci , Pier Giuseppe Pelicci

View PDF Chat

Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation

2003-04-03

Stephen J. Haggarty , Kathryn M. Koeller , Jason Chun Yu Wong +2 more

Protein acetylation, especially histone acetylation, is the subject of both research and clinical investigation. At least four small-molecule histone deacetylase inhibitors are currently in clinical trials for the treatment of … Protein acetylation, especially histone acetylation, is the subject of both research and clinical investigation. At least four small-molecule histone deacetylase inhibitors are currently in clinical trials for the treatment of cancer. These and other inhibitors also affect microtubule acetylation. A multidimensional, chemical genetic screen of 7,392 small molecules was used to discover “tubacin,” which inhibits α-tubulin deacetylation in mammalian cells. Tubacin does not affect the level of histone acetylation, gene-expression patterns, or cell-cycle progression. We provide evidence that class II histone deacetylase 6 (HDAC6) is the intracellular target of tubacin. Only one of the two catalytic domains of HDAC6 possesses tubulin deacetylase activity, and only this domain is bound by tubacin. Tubacin treatment did not affect the stability of microtubules but did decrease cell motility. HDAC6 overexpression disrupted the localization of p58, a protein that mediates binding of Golgi elements to microtubules. Our results highlight the role of α-tubulin acetylation in mediating the localization of microtubule-associated proteins. They also suggest that small molecules that selectively inhibit HDAC6-mediated α-tubulin deacetylation, a first example of which is tubacin, might have therapeutic applications as antimetastatic and antiangiogenic agents.

View PDF Chat

Histone Deacetylase Inhibitors: Overview and Perspectives

2007-10-01

Milos Dokmanovic , Cathy Clarke , Paul A. Marks

Abstract Histone deacetylase inhibitors (HDACi) comprise structurally diverse compounds that are a group of targeted anticancer agents. The first of these new HDACi, vorinostat (suberoylanilide hydroxamic acid), has received Food … Abstract Histone deacetylase inhibitors (HDACi) comprise structurally diverse compounds that are a group of targeted anticancer agents. The first of these new HDACi, vorinostat (suberoylanilide hydroxamic acid), has received Food and Drug Administration approval for treating patients with cutaneous T-cell lymphoma. This review focuses on the activities of the 11 zinc-containing HDACs, their histone and nonhistone protein substrates, and the different pathways by which HDACi induce transformed cell death. A hypothesis is presented to explain the relative resistance of normal cells to HDACi-induced cell death. (Mol Cancer Res 2007;5(10):981–9)

Histone Deacetylases Associated with the mSin3 Corepressor Mediate Mad Transcriptional Repression

1997-05-01

Carol D. Laherty , Wen‐Ming Yang , Jian-Min Sun +3 more

A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations

2010-04-01

Sreenath V. Sharma , Diana Lee , Bihua Li +7 more

View PDF Chat

Sodium butyrate inhibits histone deacetylation in cultured cells

1978-05-01

E. Peter M. Candido

Histone deacetylases (HDACs): characterization of the classical HDAC family

2003-03-12

Annemieke J.M. de Ruijter , Albert H. Gennip , Huib N. Caron +2 more

Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as methylation, phosphorylation and acetylation. … Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as methylation, phosphorylation and acetylation. Acetylation is probably the best understood of these modifications: hyperacetylation leads to an increase in the expression of particular genes, and hypoacetylation has the opposite effect. Many studies have identified several large, multisubunit enzyme complexes that are responsible for the targeted deacetylation of histones. The aim of this review is to give a comprehensive overview of the structure, function and tissue distribution of members of the classical histone deacetylase (HDAC) family, in order to gain insight into the regulation of gene expression through HDAC activity. SAGE (serial analysis of gene expression) data show that HDACs are generally expressed in almost all tissues investigated. Surprisingly, no major differences were observed between the expression pattern in normal and malignant tissues. However, significant variation in HDAC expression was observed within tissue types. HDAC inhibitors have been shown to induce specific changes in gene expression and to influence a variety of other processes, including growth arrest, differentiation, cytotoxicity and induction of apoptosis. This challenging field has generated many fascinating results which will ultimately lead to a better understanding of the mechanism of gene transcription as a whole.

View PDF Chat

The many roles of histone deacetylases in development and physiology: implications for disease and therapy

2008-12-09

Michael Haberland , Rusty L. Montgomery , Eric N. Olson

View PDF Chat

Molecular Evolution of the Histone Deacetylase Family: Functional Implications of Phylogenetic Analysis

2004-03-10

IvanV Gregoretti , Yunmi Lee , Holly V. Goodson

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

2014-04-01

Ed Seto , Minoru Yoshida

Edward Seto1 and Minoru Yoshida2 1Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612 2Chemical Genetics Laboratory, RIKEN, Wako, Saitama 351-0198, Japan Correspondence: ed.seto{at}moffitt.org Edward Seto1 and Minoru Yoshida2 1Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612 2Chemical Genetics Laboratory, RIKEN, Wako, Saitama 351-0198, Japan Correspondence: ed.seto{at}moffitt.org

View PDF Chat

New and emerging HDAC inhibitors for cancer treatment

2014-01-01

Alison C. West , Ricky W. Johnstone

Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the … Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the rapid development of small-molecule inhibitors that target the cancer epigenome. Herein, we discuss the influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis. We examine HDAC inhibitors (HDACis) targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents following the FDA approval of two HDACis, vorinostat and romidepsin.

View PDF Chat

Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells

2001-12-17

Martin Göttlicher

Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases

2011-01-01

Wei Xu , Hui Yang , Ying Liu +7 more

View PDF Chat

Histone Deacetylase Inhibitors: Inducers of Differentiation or Apoptosis of Transformed Cells

2000-08-02

P A Marks , Victoria M. Richon , Richard A. Rifkind

Histone deacetylase (HDAC) inhibitors have been shown to be potent inducers of growth arrest, differentiation, and/or apoptotic cell death of transformed cells in vitro and in vivo. One class of … Histone deacetylase (HDAC) inhibitors have been shown to be potent inducers of growth arrest, differentiation, and/or apoptotic cell death of transformed cells in vitro and in vivo. One class of HDAC inhibitors, hydroxamic acid-based hybrid polar compounds (HPCs), induce differentiation at micromolar or lower concentrations. Studies (x-ray crystallographic) showed that the catalytic site of HDAC has a tubular structure with a zinc atom at its base and that these HDAC inhibitors, such as suberoylanilide hydroxamic acid and trichostatin A, fit into this structure with the hydroxamic moiety of the inhibitor binding to the zinc. HDAC inhibitors cause acetylated histones to accumulate in both tumor and normal tissues, and this accumulation can be used as a marker of the biologic activity of the HDAC inhibitors. Hydroxamic acid-based HPCs act selectively to inhibit tumor cell growth at levels that have little or no toxicity for normal cells. These compounds also act selectively on gene expression, altering the expression of only about 2% of the genes expressed in cultured tumor cells. In general, chromatin fractions enriched in actively transcribed genes are also enriched in highly acetylated core histones, whereas silent genes are associated with nucleosomes with a low level of acetylation. However, HDACs can also acetylate proteins other than histones in nucleosomes. The role that these other targets play in the induction of cell growth arrest, differentiation, and/or apoptotic cell death has not been determined. Our working hypothesis is that inhibition of HDAC activity leads to the modulation of expression of a specific set of genes that, in turn, result in growth arrest, differentiation, and/or apoptotic cell death. The hydroxamic acid-based HPCs are potentially effective agents for cancer therapy and, possibly, cancer chemoprevention.

Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors

1999-09-01

Michael S. Finnin , Jill R. Donigian , Alona Cohen +5 more

Inhibition of Histone Deacetylase Activity by Butyrate

2003-07-01

James Davie

View PDF Chat

ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation

2009-05-21

Kathryn E. Wellen , Georgia Hatzivassiliou , Uma M. Sachdeva +3 more

Histone acetylation in single-cell eukaryotes relies on acetyl coenzyme A (acetyl-CoA) synthetase enzymes that use acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have … Histone acetylation in single-cell eukaryotes relies on acetyl coenzyme A (acetyl-CoA) synthetase enzymes that use acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure only to low concentrations of extracellular acetate. We have shown that histone acetylation in mammalian cells is dependent on adenosine triphosphate (ATP)-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.

View PDF Chat

FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma

2007-10-01

Bhupinder Mann , John R. Johnson , Martin H. Cohen +2 more

Learning Objectives After completing this course, the reader will be able to: Add vorinostat to the armamentarium of drugs for CTCL.Identify the mechanism of action of vorinostat.Identify goals of therapy … Learning Objectives After completing this course, the reader will be able to: Add vorinostat to the armamentarium of drugs for CTCL.Identify the mechanism of action of vorinostat.Identify goals of therapy of CTCL.Identify active CTCL therapies.Identify CTCL response criteria. Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com

View PDF Chat

The role of histone deacetylases (HDACs) in human cancer

2007-03-07

Santiago Ropero , Manel Esteller

View PDF Chat

Histone deacetylase inhibitor selectively induces p21 WAF1 expression and gene-associated histone acetylation

2000-08-22

Victoria M. Richon , Todd W. Sandhoff , Richard A. Rifkind +1 more

Histone deacetylases (HDACs) catalyze the removal of acetyl groups on the amino-terminal lysine residues of core nucleosomal histones. This activity is associated generally with transcriptional repression. We have reported previously … Histone deacetylases (HDACs) catalyze the removal of acetyl groups on the amino-terminal lysine residues of core nucleosomal histones. This activity is associated generally with transcriptional repression. We have reported previously that inhibition of HDAC activity by hydroxamic acid-based hybrid polar compounds, such as suberoylanilide hydroxamic acid (SAHA), induces differentiation and/or apoptosis of transformed cells in vitro and inhibits tumor growth in vivo . SAHA is a potentially new therapeutic approach to cancer treatment and is in Phase I clinical trials. In several tumor cell lines examined, HDAC inhibitors alter the expression of less than 1% of expressed genes, including the cell cycle kinase inhibitor p21 WAF1 . In T24 bladder carcinoma cells, SAHA induces up to a 9-fold increase in p21 WAF1 mRNA and protein, which is, at least in part, because of an increase in the rate of transcription of the gene. SAHA causes an accumulation of acetylated histones H3 and H4 in total cellular chromatin by 2 h, which is maintained through 24 h of culture. An increase in the accumulation of acetylated H3 and H4 was detected throughout the p21 WAF1 promoter and the structural gene after culture with SAHA. The level of histone acetylation did not change in chromatin associated with the actin and p27 genes, and their mRNA expression was not altered during culture of T24 cells with SAHA. Thus, the present findings indicate that the induction of p21 WAF1 by SAHA is regulated, at least in part, by the degree of acetylation of the gene-associated histones and that this induced increase in acetylation is gene selective.

View PDF Chat

The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men

2008-02-22

Xiang-Jiao Yang , Edward Seto

HDACs and HDAC Inhibitors in Cancer Development and Therapy

2016-09-06

Yixuan Li , Edward Seto

Yixuan Li and Edward Seto George Washington University Cancer Center, Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC 20037 Correspondence: seto{at}gwu.edu Yixuan Li and Edward Seto George Washington University Cancer Center, Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC 20037 Correspondence: seto{at}gwu.edu

View PDF Chat

Combination therapy in combating cancer

2017-03-30

Reza Bayat Mokhtari , Tina S. Homayouni , Narges Baluch +4 more

// Reza Bayat Mokhtari 1,2,4 , Tina S. Homayouni 1 , Narges Baluch 3 , Evgeniya Morgatskaya 1 , Sushil Kumar 1 , Bikul Das 4 and Herman Yeger 1,2 … // Reza Bayat Mokhtari 1,2,4 , Tina S. Homayouni 1 , Narges Baluch 3 , Evgeniya Morgatskaya 1 , Sushil Kumar 1 , Bikul Das 4 and Herman Yeger 1,2 1 Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada 2 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 3 Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada 4 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, Massachusetts, USA Correspondence to: Herman Yeger, email: // Reza Bayat Mokhtari, email: // Keywords : Nrf2-Keap1, HIF-1alpha, carbonic anhydrase 9 (CAIX), histone deacetylase inhibitor (HDACi), carbonic anhydrase inhibitor (CAI) Received : October 19, 2016 Accepted : February 27, 2017 Published : March 30, 2017 Abstract Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. The 5-year survival rates for most metastatic cancers are still quite low, and the process of developing a new anti-cancer drug is costly and extremely time-consuming. Therefore, new strategies that target the survival pathways that provide efficient and effective results at an affordable cost are being considered. One such approach incorporates repurposing therapeutic agents initially used for the treatment of different diseases other than cancer. This approach is effective primarily when the FDA-approved agent targets similar pathways found in cancer. Because one of the drugs used in combination therapy is already FDA-approved, overall costs of combination therapy research are reduced. This increases cost efficiency of therapy, thereby benefiting the “medically underserved”. In addition, an approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden. In this systematic review, we discuss important pathways commonly targeted in cancer therapy. Furthermore, we also review important repurposed or primary anti-cancer agents that have gained popularity in clinical trials and research since 2012.

View PDF Chat

Histone Deacetylase Inhibitors as Anticancer Drugs

2017-07-01

Tomáš Eckschlager , Johana Plch , Marie Stiborová +1 more

Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is … Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

View PDF Chat

SNAI2 cooperates with MEK1/2 and HDACs to suppress BIM- and BMF-dependent apoptosis in TERT promoter mutant cancers

2025-06-25

Amol Tandon , Josh Lewis Stern | PLoS ONE

Cancers with TERT promoter mutations (TPM) display elevated RAS pathway signaling and mesenchymal traits, and associate with lower patient survival rates. We examined whether RAS pathway signaling in TPM cancers … Cancers with TERT promoter mutations (TPM) display elevated RAS pathway signaling and mesenchymal traits, and associate with lower patient survival rates. We examined whether RAS pathway signaling in TPM cancers cooperates with mesenchymal features to drive resistance to apoptosis. We observed that RAS pathway signaling in TPM cancers inhibited apoptosis by downregulating the pro-apoptotic protein BIM. By using inhibitors of MEK1/2 kinases, we rescued the ability of TPM cancer cells to undergo apoptosis, which may have implications for targeted therapies. To further capitalize on this rescue, we explored combination treatments to drive apoptotic cell death. Treatment with the pan-BCL2 inhibitor, navitoclax (NX), in combination with MEK inhibition, significantly increased apoptosis, indicating that these cells are capable of undergoing intrinsic apoptosis, with BIM likely playing a critical role. Further, we found that transcriptional reprogramming of the mesenchymal state of TPM cancers using histone deacetylase inhibitors (HDACi) resulted in a synergistic increase in apoptosis, contingent upon BIM de-repression. Notably, the cause of this apoptosis appeared to be independent of DNA damage. The suppression of the mesenchymal transcription factor SNAI2, which has known roles in recruiting HDACs to silence gene expression, amplified apoptosis. Mechanistically, knockdown of SNAI2 impaired the cellular DNA repair leading to elevated basal levels of phosphorylated H2AX. Our findings show that TPM cancers exhibit specific small molecule vulnerabilities, driven by the convergence of RAS-MEK signaling and impaired HDAC regulation dependent on pro-apoptotic BH3-only proteins. Based on our findings, we propose that stratifying cancers based on TPM may identify a subset of tumors that are responsive to innovative combinations of inhibitors targeting these axes.

Correlations of serum histone deacetylase 3 and thrombospondin-1 levels with cardiac function grades, ventricular remodeling, and prognosis in patients with chronic heart failure

2025-06-24

Jianfeng Cheng , Tao Cheng | Journal of Cardiothoracic Surgery

This study aims to analyze the relations of serum Histone Deacetylase 3 (HDAC3) and Thrombospondin-1 (TSP-1) levels to cardiac function grades, ventricular remodeling, and prognosis of patients with chronic heart … This study aims to analyze the relations of serum Histone Deacetylase 3 (HDAC3) and Thrombospondin-1 (TSP-1) levels to cardiac function grades, ventricular remodeling, and prognosis of patients with chronic heart failure (CHF). We conducted a retrospective analysis of 128 enrolled CHF patients, with 102 healthy individuals as controls. Baseline data and two-year follow-up records were collected to assess prognosis. Serum levels of HDAC3 and TSP-1 were measured using ELISA, and their correlations with ventricular remodeling indicators such as LVEF, LVEDD, LVFS, BNP, NT-proBNP, and cTnI were analyzed using Pearson's correlation coefficient. No significant differences were observed among participants in terms of age, gender, BMI, comorbidities, smoking history, and drinking history. CHF patients exhibited significantly reduced LVEF and LVFS, while LVEDD, BNP, NT-proBNP, cTnI levels, and serum levels of HDAC3 and TSP-1 were markedly elevated. It was found that serum levels of HDAC3 and TSP-1 increased with worsening cardiac function. Both of them correlated significantly with ventricular remodeling indicators, and their elevation was an independent risk factor for poor prognosis in CHF patients. Serum levels of HDAC3 and TSP-1 are elevated in CHF patients, exhibiting significant correlations with ventricular remodeling indicators. Combined detection of these two markers may assist in predicting poor prognosis in CHF patients.

Hypertranslation

2025-06-23

Xiaofei Zhao , Yule Peng , Hui Yu | Social Semiotics

Contribution of histone deacetylases (HDACs) to the regulation of histone and non-histone proteins: implications for fibrotic diseases

2025-06-23

Sunyoung Jang , Nuri Choi , Jong Hoon Park +1 more | BMB Reports

HDAC3 Serine 424 phospho-mimic and phospho-null mutants bidirectionally modulate long-term memory formation and synaptic plasticity in the adult and aging mouse brain

2025-06-23

Alyssa M. Rodriguez , Enikö A. Kramár , Agatha S Augustynski +7 more | Journal of Neuroscience

Long-term memory formation is negatively regulated by histone deacetylase 3 (HDAC3), a transcriptional repressor. Emerging evidence suggests that post-translational phosphorylation of HDAC3 at its serine 424 (S424) residue is critical … Long-term memory formation is negatively regulated by histone deacetylase 3 (HDAC3), a transcriptional repressor. Emerging evidence suggests that post-translational phosphorylation of HDAC3 at its serine 424 (S424) residue is critical for its deacetylase activity in transcription. However, it remains unknown if HDAC3 S424 phosphorylation regulates the ability of HDAC3 to modulate long-term memory formation. To examine the functionality of S424, we expressed an HDAC3-S424D phospho-mimic mutant (constitutively active form) or an HDAC3-S424A phospho-null mutant (deacetylase dead form) in the dorsal hippocampus of mice. We assessed the functional consequence of these mutants on long-term memory (LTM) formation and long-term potentiation (LTP) in young adult male mice. We also assessed whether the HDAC3-S424A mutant could ameliorate age-related deficits in LTM and LTP in aging male and female mice. Results demonstrate that young adult male mice expressing the HDAC3-S424D phospho-mimic mutant in dorsal hippocampus exhibit significantly impaired LTM and LTP. In contrast, the HDAC3-S424A phospho-null mutant expressed in the hippocampus of young adult male mice enabled the transformation of subthreshold learning into robust LTM and enhanced LTP. Similarly, expression of the HDAC3-S424A mutant enabled LTM formation and enhanced LTP in aging male and aging female mice. Overall, these findings demonstrate that HDAC3 S424 is a pivotal residue that has the ability to bidirectionally regulate synaptic plasticity and LTM formation in the adult and aging brain.Significance statement Histone deacetylase 3 (HDAC3) is a negative regulator of synaptic plasticity and memory. However, the mechanism that regulates HDAC3 activity remains poorly understood. This study demonstrates the pivotal nature of Serine 424 of HDAC3 to bidirectionally regulate long-term potentiation, a form of synaptic plasticity, and long-term memory formation. Serine 424 is a phosphorylation site, suggesting that phosphorylation of HDAC3 is a key regulatory mechanism controlling its regulation of gene expression required for long-term memory. Indeed, expression of a Serine 424 phospho-null in the aging brain ameliorated age-dependent long-term synaptic plasticity and long-term memory deficits in aging male and aging female mice. Thus, this study provides new insight into the regulation of HDAC3 activity involved in cognitive processes.

Epigenetic modifiers to enhance the efficacy of immune checkpoint inhibitors for the treatment of melanoma

2025-06-23

Luigi Liguori , Angelo Luciano , Valentina Pagliara +7 more | Translational Oncology

Epigenetic Insights Into Aging: Emerging Roles of Natural Products in Therapeutic Interventions

2025-06-21

Yuepeng Pang , Huan Zhang , Huimin Li +4 more | Phytotherapy Research

ABSTRACT Aging is a significant contributor to numerous diseases and presents serious challenges to public health. Consequently, investigating the underlying mechanisms of aging and developing effective interventions to combat its … ABSTRACT Aging is a significant contributor to numerous diseases and presents serious challenges to public health. Consequently, investigating the underlying mechanisms of aging and developing effective interventions to combat its effects have become increasingly important, as achieving healthy aging has emerged as a growing priority. A primary characteristic of aging is the epigenetic changes that occur within the genome. Epigenetic regulation, functioning as a reversible mechanism, closely links gene composition to phenotype and plays a crucial role in reversing aging in response to environmental stimuli. Epigenetics involves modifying phenotype or gene expression by regulating posttranscriptional levels without altering the DNA sequence. These mechanisms are vital to the aging process and are anticipated to become key targets for delaying aging and improving or preventing age‐related diseases in the future. Recent studies have indicated that natural product therapy has emerged as one of the most promising strategies for mitigating the effects of aging. The application of natural products acting via the epigenetic regulation in therapy is particularly flexible and controllable, facilitating practical use while reducing the risk of drug resistance and enhancing host immune responses. This article reviews the current research status and advancements in epigenetic pathways within the realm of anti‐aging drugs, proposing future research directions and potential development trends. The aim is to provide a reference for researchers in the field of epigenetics while offering ideas and suggestions for subsequent studies.

Proteomics-Based Trapping to Study Substrates of Histone Deacetylase 6 Catalytic Domain 1

2025-06-21

Udana V. Ariyaratne , Valentine O. Nwanelo , Rachael Taiwo Tiamiyu +2 more | Biochemistry

Histone deacetylase 6 (HDAC6) is linked with various cellular functions, such as gene expression and protein degradation, as well as many diseases, including breast cancers and Alzheimer's disease. HDAC6 removes … Histone deacetylase 6 (HDAC6) is linked with various cellular functions, such as gene expression and protein degradation, as well as many diseases, including breast cancers and Alzheimer's disease. HDAC6 removes the acetyl group of acetyllysine from histones to regulate gene expression in the nucleus. However, with predominant localization in the cytoplasm, various cytoplasmic substrates of HDAC6 have also been identified. HDAC6 is unique among the other 11 metal-dependent HDAC family members due to the presence of two independent and active deacetylase domains. Recently, an inactive mutant of HDAC6 has been used as a trap to discover substrates of the second catalytic domain (CD2). Here, substrates of the first catalytic domain (CD1) of HDAC6 were explored using trapping mutants and proteomics analysis, with 21 putative substrates identified. Among them, the E3 ubiquitin ligase HUWE1 was validated as a novel HDAC6 substrate. Specifically, E3 ligase HUWE1 was deacetylated by HDAC6 CD1 to elevate degradation activity. HDAC6 CD1 also regulated the protein levels of E3 ligase UBR5. These studies document the interplay between protein deacetylation and degradation by HDAC6 CD1, which is consistent with a model where HDAC6 CD1-mediated deacetylation influences protein degradation via E3 ligases.

Assessment of test-retest reproducibility by [18F]Bavarostat for PET imaging of HDAC6

2025-06-21

Mika Naganawa , Ming‐Qiang Zheng , Jean‐Dominique Gallezot +7 more | EJNMMI Research

Abstract Background Histone deacetylase 6 (HDAC6) is an enzyme pivotal for gene regulation, influencing cellular pathways through protein deacetylation. HDAC6 is a potential therapeutic target in diseases such as cancer … Abstract Background Histone deacetylase 6 (HDAC6) is an enzyme pivotal for gene regulation, influencing cellular pathways through protein deacetylation. HDAC6 is a potential therapeutic target in diseases such as cancer and neurodegenerative disorders. Koole et al. investigated brain binding of [ 18 F]Bavarostat, an HDAC6 inhibitor, in healthy participants, revealing an absolute test-retest variability (aTRV) of 7.7% ( n = 4) for the distribution volume ( V T ) with a 1-day interscan interval. This study aims to evaluate test-retest reproducibility with a more extended interscan interval. Results Six participants (3 M/3F) underwent a test-retest scan, each lasting for 120 min using a 4-ring Biograph mCT PET/CT scanner. Arterial blood sampling and metabolite analysis were performed to derive the input function. The two scans were 28 ± 12 days apart (14–43 days, n = 6). Regional time-activity curves (TACs) were generated for 15 regions of interest (ROIs). Kinetic analysis of the 120-min TACs was performed using one-tissue and two-tissue compartment models (1TC, 2TC) and multilinear analysis-1 (MA1) to quantify V T values and compute absolute test-retest variability (aTRV). The effects of scan duration (60 to 120 min) and MA1 t * setting on aTRV and bias were investigated. Careful analysis of the plasma HPLC data was needed since metabolites eluted close in time to the parent. The MA1 model ( t * = 40 min) adequately described regional TACs and produced stable kinetic parameters with good agreement to 2TC (MA1 V T =0.98 × 2TC V T + 0.48, bias: -0.1%) while 1TC underestimated V T by 5.1%. Regional V T values exhibited a relatively uniform pattern, highest in the amygdala and lowest in the centrum semiovale. Individual aTRV values ranged from 2 to 9%. Scan durations between 100 and 120 min provided the most consistent results, with minimal bias and acceptable aTRV across all tested t * values. Although a 90-minute scan with t *=10 or 20-minute balanced scan time and aTRV, optimal parameters varied by brain region. Smaller regions (e.g., amygdala) required longer scans to achieve reliable V T quantification. Conclusions The test-retest variability of [ 18 F]Bavarostat V T values demonstrated favorable results for a one-month scan interval, comparable to the reported values.

Discovery and Characterization of Novel Non-Hydroxamate HDAC11 Inhibitors

2025-06-20

Aleksandra Kopranovic , Franz‐Josef Meyer‐Almes | International Journal of Molecular Sciences

Histone deacetylase 11 (HDAC11), the sole member of class IV HDACs, has gained prominence due to its unique enzymatic profile and pathological relevance in cancer, neurodegenerative, inflammatory diseases, and metabolic … Histone deacetylase 11 (HDAC11), the sole member of class IV HDACs, has gained prominence due to its unique enzymatic profile and pathological relevance in cancer, neurodegenerative, inflammatory diseases, and metabolic disorders. However, only a limited number of selective HDAC11 inhibitors have been identified, and many of these contain a potentially mutagenic hydroxamic acid as a zinc-chelating motif. Consequently, there is an imperative to identify potent and selective non-hydroxamate HDAC11 inhibitors with improved physicochemical properties. In this study, we conducted an extensive experimental high-throughput screening of 10,281 structurally diverse compounds to identify novel HDAC11 inhibitors. Two promising candidates, caffeic acid phenethyl ester (CAPE) and compound 9SPC045H03, both lacking a hydroxamic acid warhead, were discovered, showing micromolar inhibitory potency (IC50 = 1.5 and 2.3 µM, respectively), fast and reversible binding, and remarkable isozyme selectivity. Molecular docking revealed distinct zinc-chelating mechanisms involving either carbonyl oxygen (CAPE) or pyridine nitrogen (9SPC045H03), in contrast to canonical hydroxamates. Both compounds are drug-like and exhibit favorable physicochemical and pharmacokinetic profiles, particularly beneficial water solubility and good adsorption, making them valuable starting points for further optimization. These findings open new avenues for the development of selective, non-hydroxamate HDAC11 inhibitors with potential therapeutic applications.

Genetic deletion of histone deacetylase 6 prevents peritoneal fibrosis via suppression of heat shock protein 90 deacetylation

2025-06-20

Yingfeng Shi , Jinqing Li , Qin Zhong +7 more | The Journal of Pathology

Abstract Peritoneal fibrosis (PF) is a serious complication contributing to ultrafiltration failure in patients undergoing peritoneal dialysis that currently lacks effective treatment strategies. Our recent studies highlighted the key role … Abstract Peritoneal fibrosis (PF) is a serious complication contributing to ultrafiltration failure in patients undergoing peritoneal dialysis that currently lacks effective treatment strategies. Our recent studies highlighted the key role of histone deacetylase 6 (HDAC6) in the development of PF. To better understand the mechanisms underlying the involvement of HDAC6 in PF, we conducted in vivo experiments using Hdac6 KO mice and in vitro studies using human peritoneal mesothelial cells (HPMCs). Our results demonstrated that HDAC6 gene silencing improved PF and angiogenesis in vivo and altered pathological phenotypes in vitro . In Hdac6 KO mice, the key pathways regulating extracellular matrix accumulation, angiogenesis, and secretion of inflammatory cytokines (including TGFB1/SMAD3, HIF‐1α/VEGFR‐2/MAPK3/MAPK1, and TLR4/NF‐κB pathways) were inhibited. We also identified heat shock protein 90 (HSP90) as the substrate of HDAC6 in both PF mice and HPMCs and demonstrated that HDAC6 exerted its regulatory function in PF through the deacetylation of HSP90. Overall, our study provides novel insights into the critical role of the HDAC6‐HSP90 interplay in PF using Hdac6 KO mice. We identify HSP90 as an essential substrate through which HDAC6 exerts its function in PF, providing an experimental basis for the development of novel therapeutic strategies. © 2025 The Pathological Society of Great Britain and Ireland.

Development of tetrahydro-γ-carboline-based histone deacetylase inhibitors with antitumor activities

2025-06-19

Zeyi Wan , Xiangzhi Li , Yuhua Qu +5 more | Monatshefte für Chemie - Chemical Monthly

Harnessing Dietary Phytochemicals to Modulate Signaling Pathways in Cancer Chemoprevention—A Review

2025-06-18

Kritika Pandit , Chandni Garg , Aashaq Hussain Bhat +2 more | Phytotherapy Research

ABSTRACT Cancer chemoprevention involves the use of natural or synthetic agents to delay, suppress, or reverse cancer progression. Among natural sources, phytochemicals derived from medicinal plants have garnered significant attention … ABSTRACT Cancer chemoprevention involves the use of natural or synthetic agents to delay, suppress, or reverse cancer progression. Among natural sources, phytochemicals derived from medicinal plants have garnered significant attention due to their potent biological effects on human health, particularly in combating various cancer types. These compounds offer a promising alternative to traditional therapeutic approaches by targeting key mechanisms involved in cancer development. Their natural origin, minimal side effects, and diverse modes of action make them valuable candidates for cancer prevention strategies. This review highlights the diverse mechanisms by which plant‐derived compounds exert chemopreventive effects, including cell cycle arrest, induction of apoptosis, and activation of autophagy. Additionally, it explores their ability to reverse adverse epigenetic modifications, enhance the expression of phase II detoxification enzymes, and modulate critical signaling pathways involved in tumor progression. Understanding these molecular mechanisms is essential for optimizing the therapeutic potential of phytochemicals and expanding their clinical applications. By emphasizing the multifaceted role of phytochemicals in cancer chemoprevention, the review underscores their significance in developing novel anticancer therapeutics. These plant‐derived compounds hold great promise in shaping future cancer treatment paradigms through their ability to modulate key cellular processes and signaling pathways. Addressing existing research gaps could pave the way for more extensive studies and clinical trials, ultimately leading to the development of effective, plant‐based anticancer therapies.

Novel Heterocyclic 5H-Dibenzo[b,f]azepine Derivatives as Selective HDAC6 Inhibitors for Treatment of Charcot Marie Tooth Disease

2025-06-18

Steven H. Liang | ACS Medicinal Chemistry Letters

NUCKS1 promotes invasion and metastasis of colorectal cancer by stabilizing HDAC2 and activating AKT

2025-06-17

Liaoliao Zhu , Ting Zhao , Haichuan Su +5 more | Oncogenesis

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) functions as an oncogene in colorectal cancer (CRC), promotes the progression of CRC, and is associated with poor prognosis in patients. … Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) functions as an oncogene in colorectal cancer (CRC), promotes the progression of CRC, and is associated with poor prognosis in patients. Studies have found that NUCKS1 promotes tumor cell metastasis, yet its role in CRC invasion and metastasis remains unclear. Our findings revealed higher NUCKS1 expression in metastatic CRC compared to non-metastatic samples. Upregulation of NUCKS1 expression promoted the migration and invasion of CRC cells, while knockdown of NUCKS1 significantly inhibited the migration and invasion of CRC cells. Mechanistically, NUCKS1 was initially found to upregulate HDAC2 expression by inhibiting the lysosomal pathway, activating AKT, and thus promoting CRC invasion and metastasis. Moreover, HDAC2 inhibitor Santacruzamate A or AKT inhibitor LY294002 rescued the migration and invasion of CRC cells caused by NUCKS1 overexpression. In vivo, by injecting CRC cells into the tail vein of a nude mouse model, we found that overexpression of NUCKS1-induced lung and liver metastasis was suppressed by HDAC2 knockdown or intraperitoneal administration of the HDAC2 inhibitor Santacruzamate A. Meanwhile, AKT inhibitor LY294002 significantly inhibited lung and liver metastasis caused by overexpression of HDAC2. The expression levels of NUCKS1, HDAC2, and phosphorylated AKT were significantly positively correlated in human CRC tissues. These findings suggest that NUCKS1 contributes to CRC invasion and metastasis by stabilizing HDAC2 and activating AKT, highlighting NUCKS1 and HDAC2 as potential therapeutic targets for CRC.

Current and Emerging Prodrug Strategies

2025-06-17

Dean G. Brown , Hyejin Park | Journal of Medicinal Chemistry

An analysis of recent prodrugs reported in the literature is discussed. The range of strategies includes ProTide technologies, esters, phosphates, cell-targeting approaches, pH-dependent approaches, and newer technologies such as photo- … An analysis of recent prodrugs reported in the literature is discussed. The range of strategies includes ProTide technologies, esters, phosphates, cell-targeting approaches, pH-dependent approaches, and newer technologies such as photo- and radiation-activated prodrugs. Many successful prodrug approaches have been a result of the first three examples, which appear to be well established. One area of significant impact for prodrug technology has been with anti-infectives. This area is discussed in detail with learnings and innovations that can be applied to other disease areas. Finally, the prodrug strategy is discussed in the context of both reactive and proactive applications. If used as a rescue strategy for a failed clinical candidate, it can be potentially costly and time-consuming. Proactive prodrug strategies should be considered in the early phase of drug discovery programs, especially in cases in which chemotype properties or target-based risks may compromise the desired route of administration.

Evolving Resistance: The Interplay of p53, Chemoresistance, and Metastasis in Cancer's Journey

2025-06-17

Zenith Kwong | MedScien

Cancer is a growing concern around the world with more than 20 million new cases confirmed and counting. This is partly caused by the overuse of Chemotherapeutic drugs against Cancer, … Cancer is a growing concern around the world with more than 20 million new cases confirmed and counting. This is partly caused by the overuse of Chemotherapeutic drugs against Cancer, leading to its potency. Cancer starts with an accumulation of genetic mutations in the genome, and the ignorance to cell checks by CD8 and NK cells. The Cancer cell utilizes its hallmark capabilities and uses one of its cells to metastasizes in other areas of the body either through the perineural, circulatory, or lymphatic system. p53 is a tumor suppressor gene which repairs the mutations of the cell by conducting cell cycle arrest and inducing apoptosis. However, cancer cells can increase the expression of SB100 which can inhibit p53. One solution is to combine PRIMA-1 and CDDP which restores p53 and it’s wild type functions to induce apoptosis. This effect is increased with the use of adenoviral DN-Akt since it could increase p53 phosphorylation at Ser15.

HDAC1 deacetylates PGC-1α and its inhibition improves glucose homeostasis in diet-induced obese mice

2025-06-16

Chaim Atay Fainshtein , Or Maalumi , Katrina R. DeLeon +2 more | AJP Endocrinology and Metabolism

Excessive hepatic glucose production (HGP) driven by increased gluconeogenesis is a hallmark of type 2 diabetes, making its inhibition a crucial strategy for reducing hyperglycemia. Central to HGP regulation is … Excessive hepatic glucose production (HGP) driven by increased gluconeogenesis is a hallmark of type 2 diabetes, making its inhibition a crucial strategy for reducing hyperglycemia. Central to HGP regulation is the transcriptional co-activator PGC-1α, which promotes the expression of key gluconeogenic enzymes. The acetylation state of PGC-1α significantly influences its coactivating potential, with increased acetylation—whether induced genetically or chemically—shown to suppress its gluconeogenic activity and lower hyperglycemia. The delicate balance between specific acetyltransferases and deacetylases determines the acetylation status of PGC-1α and, consequently, its activity. While the role of sirtuin deacetylases in PGC-1α acetylation has been extensively studied, zinc-dependent histone deacetylases (HDACs) have received less attention in this context. In this study, we demonstrate that HDAC1 strongly deacetylates PGC-1α, enhancing its ability to coactivate the transcription factor HNF4α. Furthermore, we show that depleting Hdac1 in mouse primary hepatocytes and liver tissue reduces glucose production, consistent with decreased PGC-1α activity. While the HDAC family has been investigated for their contributions to metabolic homeostasis, our findings reveal a specific mechanistic pathway by which HDAC1 modulates glucose homeostasis.

Histone Deacetylase Inhibition in Alzheimer’s Disease: Molecular Mechanisms, Therapeutic Potential, and Future Perspectives

2025-06-16

Nachiket Joshi , Prachee Khadse , Shivani Jadhav +1 more | Current Topics in Medicinal Chemistry

Abstract: Alzheimer’s disease (AD) remains a formidable challenge in modern medicine, with limited therapeutic options available to combat its progressive cognitive decline. Histone acetylation is a key epigenetic mechanism responsible … Abstract: Alzheimer’s disease (AD) remains a formidable challenge in modern medicine, with limited therapeutic options available to combat its progressive cognitive decline. Histone acetylation is a key epigenetic mechanism responsible for gene expression, cell growth, and differentiation. HDAC is a group of enzymes that can reverse the acetylation of cells. These enzymes have been evidenced to be involved in the pathophysiology of AD. Hence, inhibition of this enzyme was postulated to exhibit pronounced benefits in AD concerning memory, learning, and cognition. Pan-HDAC inhibitors inhibited multiple HDAC isoforms but were associated with certain side effects. Hence, class-specific and isoform-specific inhibitors were discovered, revealing great potencies and proving efficacious. This review article comprehensively explores the evolving landscape of research avenues targeting HDAC inhibitors against AD. Beginning with the molecular mechanisms underlying AD pathology, we delve into the intricate roles of HDACs in neurodegeneration and synaptic dysfunction. Subsequently, we scrutinize preclinical studies investigating various HDAC inhibitors, elucidating their promising neuroprotective effects, modulation of epigenetic mechanisms, and potential for disease modification. Furthermore, we highlight the translational challenges and therapeutic opportunities in advancing HDAC inhibitors toward clinical applications for AD. By summarizing current research findings, this review aims to provide valuable insights into the burgeoning field of HDAC inhibition as a promising therapeutic strategy for combating AD, paving the way for future research directions and drug development endeavors.

Evaluating the Role of Neurogenic Locus Notch Homolog Protein 1 in Oral Cancer Progression and Therapeutic Opportunities

2025-06-16

Mostafa Ahmed Abdellah Ahmed , Tayyaba Rafiq , N. Rasheed +5 more | Cureus

Targeting inflammation-driven tumor progression with Zafirlukast via modulation of Jagged-1/Notch-1/Hes-1, Wnt-4/β-catenin, and VEGF signaling pathways in mice

2025-06-16

Asmaa Saleh , Dina F. Mansour , Nahed A Raslan +7 more | Naunyn-Schmiedeberg s Archives of Pharmacology

The novel HDAC6 inhibitor 9r induces anti-tumor responses by enhancing T cell response and inducing MHC class II signaling pathways in esophageal cancer

2025-06-14

Huiqin Kang , Hai‐Qian Nie , Ang He +7 more | International Immunopharmacology

Abstract P4-10-27: Epigenetic Drug Profiling for Breast Cancer Therapy: A Focus on Receptor Modulation and Heterogeneity

2025-06-13

Rahat Alam , Igor Bado | Clinical Cancer Research

Abstract Breast cancer is the second leading cause of cancer death in women. The primary cause of mortality is associated with the metastasis process of cancer cells to other organs. … Abstract Breast cancer is the second leading cause of cancer death in women. The primary cause of mortality is associated with the metastasis process of cancer cells to other organs. It has become obvious that epigenetic alteration plays a crucial role in breast cancer progression through the modulation of various signaling pathways. Additionally, the plastic nature of cancer cells is essential to their adaption in different metastatic sites. However, implementing epigenetic therapies in the clinic has been challenging due to the ubiquitous expression of many epigenetic factors. Here, we evaluate a library of epigenetic drugs to determine their impact on receptors commonly targeted in breast cancer. These include estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). We coupled an immuno-fluorescence imaging approach to bioluminescence imaging to capture receptor heterogeneity and the proliferation index of each epigenetic drug. So far, we have assessed 460 drugs that target various factors, including Epigenetics, JAK/STAT, DNA Damage, Angiogenesis, Cell Cycle, PI3K/Akt/mTOR and Cytoskeletal Signaling targeting and histone deacetylases (HDACs), DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), aurora kinase PARP, Sirtiin, EGFR, JAK, Plm pathways. We also analyzed the expression of key epigenetic markers (e.g., EZH2) and stemness-associated factors (e.g., SOX9). As a result, we found BIO, an inhibitor of GSK-3 and JAK, increases ER expression. Similarly, Curcumin, an inhibitor of p300 histone acetyl-transferase and Histone deacetylase (HDAC) promotes a broader range of factors, including Her2, Sox9, and ER. Interestingly, (+)-JQ1(BET bromodomain inhibitor), I-BRD9 (BRD9 inhibitor) and CUDC-101 (HDAC inhibitor) drastically reduced Ki67 level. Overall, these findings suggest a potential for combination therapy. While further investigation of these promising candidates is needed (3D, ex vivo, and in vivo testing), this investigation reveals new possibilities to overcome therapeutic resistance in breast cancer. Citation Format: Rahat Alam, Igor Bado. Epigenetic Drug Profiling for Breast Cancer Therapy: A Focus on Receptor Modulation and Heterogeneity [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 P4-10-27.

Correction: Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma

2025-06-13

Cecilia Bandini , Elisabetta Mereu , Tina Paradžik +7 more | Experimental Hematology and Oncology

581-P: Targeting REV-ERBα to Enhance Glucose Regulation and Address Aging-Related Muscle Dysfunction

2025-06-13

Ana P. Pinto , Vítor Rosetto Muñoz , Dennys E. Cintra +4 more | Diabetes

Introduction and Objective: Skeletal muscle is pivotal for glucose uptake, accounting for over 80% of postprandial glucose clearance. Insulin resistance (IR), a precursor to type 2 diabetes (T2D), impairs this … Introduction and Objective: Skeletal muscle is pivotal for glucose uptake, accounting for over 80% of postprandial glucose clearance. Insulin resistance (IR), a precursor to type 2 diabetes (T2D), impairs this process, resulting in hyperglycemia. Aging exacerbates declines in muscle function and mass, as well as mitochondrial efficiency, with these effects further aggravated by T2D. Rev-erbα, a critical regulator of mitochondrial dynamics and muscle integrity, has emerged as a potential therapeutic target for mitigating aging-associated dysfunctions. This study explored: 1) whether activating Rev-erbα using the agonist SR9009 could improve glucose uptake in aging mice; 2) the relationship between aging and mRNA levels of clock genes in skeletal muscle; 3) the effects of physical exercise on the mRNA expression levels of skeletal muscle clock genes. Methods: Aging-resistant mice (SAMR1) and accelerated aging mice (SAMP8) were used. SAMP8 mice underwent treatment with either vehicle or SR9009 for three days and participated in a 3-week combined exercise protocol. Results: Glucose tolerance test results revealed that SR9009 treatment improved glucose regulation in SAMP8 mice, with significantly lower blood glucose levels compared to the vehicle-treated group. Moreover, aging reduced Nr1d1 and Bmal1 expression in the gastrocnemius, but not in the soleus muscle, suggesting differential effects of aging on muscle tissues. Body weight was lower in the SAMP8 group compared to the SAMR1 group. The combined physical exercise protocol improved balance, bradykinesia, maximal strength, and motor coordination, as well as mitigated the Nr1d1 reduction in the gastrocnemius of SAMP8 mice. Conclusion: Overall, Rev-erbα activation can influence glucose metabolism in aging and highlight the complex relationship between Rev-erbα signaling and muscle health. Disclosure A.S. Pinto: None. V.R. Muñoz: None. D.E. Cintra: None. E.R. Ropelle: None. J.R. Pauli: None. E.C. Freitas: None. A.S.R. da Silva: None. Funding This study was financed, in part, by the S?o Paulo Research Foundation (FAPESP; process numbers 19/11820-5, 21/08693-1, and 21/08692-5) and by the National Council for Scientific and Technological Development (CNPq; process number 308999/2022-3).This study was financed, in part, by the Sao Paulo Research Foundation (FAPESP; process numbers 19/11820-5, 21/08693-1, and 21/08692-5) and by the National Council for Scientific and Technological Development (CNPq; process number 308999/2022-3).

Abstract P1-04-21: Suppressing suppression: histone deacetylase inhibition primes the metastatic tumor microenvironment to respond to checkpoint inhibition by dynamic rewiring of cell interactions

2025-06-13

Evanthia T. Roussos Torres , Edgar Gonzalez , Jesse Kreger +7 more | Clinical Cancer Research

Abstract Immune checkpoint inhibition (ICI) is a type of immunotherapy that has been shown to promote durable responses in a minority of patients with metastatic, triple negative breast cancer expressing … Abstract Immune checkpoint inhibition (ICI) is a type of immunotherapy that has been shown to promote durable responses in a minority of patients with metastatic, triple negative breast cancer expressing programmed death receptor ligand 1 (PD-L1), and only in combination with chemotherapy. In the breast expansion cohort of our Phase Ib trial (NCI-9844) we found that the combination of histone deacetylase inhibitor, entinostat, with dual ICI (anti-PD1 and anti-CTLA4), is safe, and led to a 25% objective response rate in heavily pretreated patients with metastatic HER2 negative breast cancer with expected rates of irAEs. In addition, our preclinical studies support response in triple negative and HER2 positive mouse models of breast cancer. Evaluation of changes in the breast tumor microenvironment (TME) from these models revealed that decreased infiltration or suppression of myeloid derived suppressor cells (MDSCs) by entinostat is a potential mechanism of action. Here, we examined breast-to lung metastases from both HER2 positive and triple negative metastatic mouse models, Neu-N and 4T1, to gain a comprehensive understanding of changes to the tumor immune microenvironment within the metastatic niche induced by treatment with entinostat, and perpetuated following treatment combination with dual ICI. Single cell RNA sequencing of treated lung metastasis confirmed decreased granulocytic-MDSCs (G-MDSC) as seen in previous studies, and revealed significant shifts in C1q macrophages, metabolically activated macrophages, classic dendritic cells, activated and primed Th2 T cells, terminally differentiated T regulatory cells and some sub-populations of B cells. Multiparametric flow analysis was not concordant suggestive that functional changes are more likely contributing to mechanisms of response and decreased immune suppression. Entinostat treatment led to an increase in stemness in tumor cells and decreased mesenchymal gene expression. We then adapted cell circuit and CellChat analysis platforms to investigate cell interactions which revealed significant immune cell interactions affected by entinostat are MDSC- CD8-T cell, macrophage- CD8-T cell and NK- G-MDSC/ CD8-T cell interactions. Ligand receptor pair analysis then revealed signaling pathways controlling chemokine secretion, and cell adhesion are significantly decreased following treatment with entinostat and are preserved upon treatment with dual ICI. From this analysis, we are investigating 6 candidate targets on MDSCs and macrophages using ex-vivo suppression assays as compared to treatment with entinostat, to determine the contribution of these signaling axes in decreasing immunosuppressive function within the TME. We are also using multiplex immunohistochemistry to examine cellular interactions within breast-to-lung metastatic tumors. We will then validate findings in metastatic tumor samples from patients designated as responders from NCI-9844, treated with entinostat + dual ICI. Preliminary evaluation suggests a significant decrease in MDSC-CD8-T cell and Macrophage-CD8-T cell interaction in responders, supportive of our preclinical data. Overall, this investigation of breast-to-lung metastatic tumors reveals how entinostat decreases immune suppression via interference of MDSC and macrophage interaction with CD8-T cells as corroborated in patients who responded to treatment. Future studies will elucidate the molecular mechanisms of action and investigate the potential for identified targets as biomarkers of response and for potential as novel therapeutic targets to improve response rates in patients with advanced breast cancer. Citation Format: Evanthia Roussos Torres, Edgar Gonzalez, Jesse Kreger, Yingtong Liu, Sarah M. Shin, Arianna Barbetta, Sarah-Elisa B. Bangerth, Julie Jang, Matthew Jacobo, Batul Al-Zubeidy, Aaron G. Baugh, Vered Stearns, Roisin M. Connolly, Won Ho, Juliet Emamaullee, Adam MacLean. Suppressing suppression: histone deacetylase inhibition primes the metastatic tumor microenvironment to respond to checkpoint inhibition by dynamic rewiring of cell interactions [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 P1-04-21.

The roles of histone acetylation key enzymes HAT, HDAC and BET proteins in neuropathic pain:selection of drug targets

2025-06-13

Xingyu Wang , Huiyu Luo | Pharmacological Research

Abstract PS12-04: HDACi combined with anthracycline elicits interactions between MHC-II+ triple-negative breast cancer and CD69+CD4+Trm orchestrating synergistic immunotherapy

2025-06-13

Zehao Wang , Jingyan Xue , Bingqiu Xiu +1 more | Clinical Cancer Research

Abstract Background: Early TNBC (eTNBC) lacks biomarkers for predicting the benefits of immune checkpoint blockade (ICB). Therefore, identifying indicators for the high-benefit patients and finding synergistic target for low-benefit populations … Abstract Background: Early TNBC (eTNBC) lacks biomarkers for predicting the benefits of immune checkpoint blockade (ICB). Therefore, identifying indicators for the high-benefit patients and finding synergistic target for low-benefit populations are crucial. Tumor-associated MHC-II (tsMHC-II) are linked with the benefits of ICB in eTNBC, though the mechanisms remain to be explored. This study aimed to research the interaction mechanisms and translational targets between tsMHC-II and CD4+ T cell subgroups by NeoTennis clinical trial cohorts. Method: RNA-seq, mIHC, and spatial analysis were used to quantify MHC expression in the tumor and spatial relations within the TME. In vivo murine cohorts combined with CyTOF were utilized to elucidate the mechanisms of tsMHC-II and CD4+ Trm cells in chemo-ICB. Co-culture of cell line, organoid, and T cell were used to investigate the regulatory factors of tsMHC-II. TMA and sc-RNA seq were used to explore the clinical significance, molecular characteristics of MHC-II+ tumor. Results: The NeoTennis trial included eTNBC patients in a two-phase clinical trial involving anthracycline induction followed by sequential nab-paclitaxel and PD-1 inhibitor (Toripalimab). Analysis of baseline and anthracycline-induced biopsy samples using mIHC (Pan-CK, HLA-A, HLA-DR, CD4, CD8, CD69, Foxp3, T-bet) allowed for the clustering of patients based on MHC-I and MHC-II expression in the tumor epithelium, resulting in four subtypes. The ROC predictive model based on the outcomes and MHC subtypes was constructed to find that the MHC-I+ MHC-II+ subtype and tsMHC-II had the highest AUC scores (0.811 and 0.848, respectively), whereas the CPS was only 0.419. Meanwhile, tsMHC-II expression in the pCR group was significantly higher than in the Non-pCR group at baseline while MHC-I showed no difference. Spatial analysis revealed that CD69+CD4+ resident-memory T cells (Trm) had the strongest spatial association with MHC-II+ tumors, with this relationship being most prevalent in the pCR group. Dynamic analysis of changes before and after anthracycline showed that the proportion of MHC-II+ tumors and CD4+ Trm cells increased in the pCR group after treatment. In vivo models combined with CyTOF revealed that there was a significant increase in CD4+ Trm cells, Th1 cells, and iNOS+ macrophages in the tumor after anthracycline. After knocking out the MHC-II molecules in tumor cells, the anthracycline-induced increase in CD4+ Trm cells and Th1 cells was reduced, and the tumors grew faster than the control group. Conversely, when CD4+ T cells were depleted following doxorubicin-treated, the efficacy of sequential anti-PD1 was diminished. The above findings showed that anthracyclines could upregulate tsMHC-II, leading to the production of CD4+ Trm. Analysis of TMA from 300 cases in FDSCC and sc-RNA seq of TNBC confirmed that MHC-II+ TNBC was associated with an extremely good prognosis (HR=0.28, 95%CI=0.12-0.64; p=0.003), while 22.4% of TNBC patients had high tsMHC-II. Moreover, the tsMHC-II+ tumor cells exhibited upregulated IFN-gamma response. RNA-seq showed that patients resistant to anthracycline-induced MHC-II upregulation had highly active HDAC. In vitro, HDAC inhibitors (Entinostat) could upregulate MHC-II in TNBC cell line and PDOs, thereby promoting increased contact with CD4+ T cells. In vivo, combining anthracyclines with Entinostat increased the infiltration of CD4+ Trm cells, Th1 cells, and CD8+ T cells, and inhibited tumor proliferation, after which, sequential anti-PD1 therapy further inhibited tumor growth for a longer time. Conclusion eTNBC patients with high tsMHC-II expression benefited from neoadjuvant anthracycline with sequential anti-PD1 ICB. Anthracyclines could promote the upregulation of tsMHC-II in tumor cells and induce the production of CD4+ Trm. For anthracyclines-resistant patients, combining neoadjuvant anthracycline with HDACi could significantly enhance the effectiveness of ICB. Citation Format: Zehao Wang, Xue Jingyan, Xiu Bingqiu, Wu Jiong. HDACi combined with anthracycline elicits interactions between MHC-II+ triple-negative breast cancer and CD69+CD4+Trm orchestrating synergistic immunotherapy [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 PS12-04.

Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer

2025-06-12

Liyuan Dai , Li‐Ling Huang , Lin Li +3 more | Respiratory Research

Promoter Hyper-methylation of ZNF662 Restrains its Tumor Suppressing Function in Triple-Negative Breast Cancer Through Regulating NGF Signaling Axis

2025-06-12

Renjie Yu , Xi Peng , Zhaobo Cheng +7 more | International Journal of Biological Sciences

Comprehensive multi-omics analysis of histone acetylation modulators identifies ASH1L as a novel aggressive marker for osteosarcoma

2025-06-12

Chenlie Ni , Qiwen Sun , Haibo Yin | Discover Oncology

HDAC7 promotes renal cancer progression by reprogramming branched-chain amino acid metabolism

2025-06-06

Hyeyoung Nam , Anirban Kundu , Suman Karki +7 more | Science Advances

Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits notable metabolic reprogramming. We previously reported elevated HDAC7, a class II histone deacetylase, in ccRCC. Here, … Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits notable metabolic reprogramming. We previously reported elevated HDAC7, a class II histone deacetylase, in ccRCC. Here, we demonstrate that HDAC7 promotes aggressive phenotypes and in vivo tumor progression in RCC. HDAC7 suppresses the expression of genes mediating branched-chain amino acid (BCAA) catabolism. Notably, lower expression of BCAA catabolism genes is strongly associated with worsened survival in ccRCC. Suppression of BCAA catabolism promotes expression of SNAIL1, a central mediator of aggressive phenotypes including migration and invasion. HDAC7-mediated suppression of the BCAA catabolic program promotes SNAI1 messenger RNA transcription via NOTCH signaling activation. Collectively, our findings provide innovative insights into the role of metabolic remodeling in ccRCC tumor progression.

Anticancer activity of RM-3-22: a TAZQ-based hydroxamic acid derivative targeting NSCLC in vitro and in vivo

2025-06-05

Essha Chatterjee , Ram Sharma , Biswajit Dey +7 more | Frontiers in Pharmacology

Introduction Lung cancer remains the leading cause of cancer-related deaths, necessitating novel therapeutic strategies. In this study, we developed RM-3-22, a TAZQ-based hydroxamic acid derivative with histone deacetylase (HDAC) inhibitory … Introduction Lung cancer remains the leading cause of cancer-related deaths, necessitating novel therapeutic strategies. In this study, we developed RM-3-22, a TAZQ-based hydroxamic acid derivative with histone deacetylase (HDAC) inhibitory properties. We evaluated its anticancer activity in non-small cell lung cancer (NSCLC), using A549 adenocarcinoma cells as the primary model. Methods The anticancer efficiency of RM-3-22 was assessed in 2D and 3D cell culture models. Cell survivalism was analysed by MTT assay. Different microscopical staining methods, including acridine orange and DAPI, were employed to evaluate autophagy, nuclear changes, and apoptosis. Cell cycle progression, mitochondrial membrane potential, and apoptosis-necrosis profiles were assessed using flow cytometry. Protein and gene expression related to the RM-3-22 induced pathway were evaluated via immunofluorescence (IF), Western blotting, and RT-PCR. Functional gene analysis was performed using siRNA-mediated knockdown. Different in silico studies were also conducted to check the clinical relevance and expression pattern of the RM-3-22-induced gene. Additionally, the in vivo efficiency of the molecule was evaluated using the NOD/SCID xenograft model. Results RM-3-22 potentially suppressed cell viability and decreased the tumor spheroid size of A549s in vitro. It induced autophagy via downregulation of PI3K/Akt/mTOR signalling pathway. Besides, flow cytometry confirmed increased apoptotic cell population and decreased mitochondrial membrane potential due to the exposure of RM-3-22. RM-3-22 also promoted G2/M arrest. Signalling cascade confirmed that autophagy regulates RM-3-22-mediated apoptosis and cell cycle arrest. Additionally, RM-3-22 upregulated FTH1, a tumor suppressor, reinforcing its anticancer potential. Notably, RM-3-22 exhibited lower toxicity to normal cells, underscoring its selectivity. In vivo, RM-3-22 markedly reduced tumor growth in the xenograft mouse model. Conclusion RM-3-22 demonstrates potent anticancer activity through different mechanisms, including inhibition of the PI3K/Akt/mTOR pathway and activation of autophagy, apoptosis, and cell cycle arrest. Further, in vivo validation also supports that RM-3-22 represents a promising therapeutic candidate against lung cancer.