Histone Deacetylase Inhibitors as Anticancer Drugs.
01 Jul 2017-International Journal of Molecular Sciences (Multidisciplinary Digital Publishing Institute (MDPI))-Vol. 18, Iss: 7, pp 1414
TL;DR: Different classes of HDAC inhibitors, mechanisms of their actions and novel results of preclinical and clinical studies are summarized, including the combination with other therapeutic modalities are discussed.
Abstract: 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.
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TL;DR: The research thus far on HDACi in combination therapy, with other anticancer agents and their translation into preclinical and clinical studies is summarized and potential biomarkers to either select or predict a patient’s response to these agents are discussed, in order to limit the off-target toxicity associated withHDACi.
Abstract: Genetic and epigenetic changes in DNA are involved in cancer development and tumor progression. Histone deacetylases (HDACs) are key regulators of gene expression that act as transcriptional repressors by removing acetyl groups from histones. HDACs are dysregulated in many cancers, making them a therapeutic target for the treatment of cancer. Histone deacetylase inhibitors (HDACi), a novel class of small-molecular therapeutics, are now approved by the Food and Drug Administration as anticancer agents. While they have shown great promise, resistance to HDACi is often observed and furthermore, HDACi have shown limited success in treating solid tumors. The combination of HDACi with standard chemotherapeutic drugs has demonstrated promising anticancer effects in both preclinical and clinical studies. In this review, we summarize the research thus far on HDACi in combination therapy, with other anticancer agents and their translation into preclinical and clinical studies. We additionally highlight the side effects associated with HDACi in cancer therapy and discuss potential biomarkers to either select or predict a patient's response to these agents, in order to limit the off-target toxicity associated with HDACi.
451 citations
Cites background from "Histone Deacetylase Inhibitors as A..."
...HDACi have pleiotropic cellular effects (Figure 2) and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest (13, 15, 19, 25, 26)....
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TL;DR: A comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification is conducted, which presents all the approved drugs as well as important drug candidates in clinical trials for each target, and discusses the current challenges.
Abstract: Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.
398 citations
TL;DR: This review has endeavored to showcase how a "multitargeted" approach to drug design has led to new families of metallodrugs which may not only reduce systemic toxicities associated with modern day chemotherapeutics but also address resistance issues that are plaguing many Chemotherapeutic regimens.
Abstract: While medicinal inorganic chemistry has been practised for over 5000 years, it was not until the late 1800s when Alfred Werner published his ground-breaking research on coordination chemistry that we began to truly understand the nature of the coordination bond and the structures and stereochemistries of metal complexes. We can now readily manipulate and fine-tune their properties. This had led to a multitude of complexes with wide-ranging biomedical applications. This review will focus on the use and potential of metal complexes as important therapeutic agents for the treatment of cancer. With major advances in technologies and a deeper understanding of the human genome, we are now in a strong position to more fully understand carcinogenesis at a molecular level. We can now also rationally design and develop drug molecules that can either selectively enhance or disrupt key biological processes and, in doing so, optimize their therapeutic potential. This has heralded a new era in drug design in which we a...
389 citations
TL;DR: This perspective reviews the biological and medicinal chemistry advances over the last three decades with an emphasis on the design of selective inhibitors that discriminate between the eleven human HDAC isoforms.
Abstract: It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms
279 citations
TL;DR: Significant developments within the last six years on the application of rhenium, osmium, and iridium complexes as anticancer drug candidates are summarized.
Abstract: The clinical success of the platinum-based chemotherapeutic agents has prompted the investigation of coordination and organometallic complexes of alternative metal centers for use as anticancer agents. Among these alternatives, the third row transition metal neighbors of platinum on the periodic table have only recently been explored for their potential to yield anticancer-active complexes. In this Perspective, we summarize developments within the last six years on the application of rhenium, osmium, and iridium complexes as anticancer drug candidates. This review focuses on studies that discuss the potential mechanisms of action of these complexes. As reflected in this Perspective, complexes of these metal ions induce cancer cell death via a diverse range of mechanisms. Notably, small structural changes can significantly alter the mode of cell death, hindering efforts to elucidate structure–activity relationships. This property may both benefit and hinder the clinical development of these compounds.
178 citations
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Abstract: Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.
5,129 citations
"Histone Deacetylase Inhibitors as A..." refers background in this paper
...The Wnt signaling pathway plays an important role in various cancers such as colon, breast, ovarian, prostate and endometrial cancers as well as medulloblastoma and melanoma [103]....
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TL;DR: It is demonstrated that the serine/threonine protein kinase Akt/PKB mediates the activation of eNOS, leading to increased NO production, and represents a novel Ca2+-independent regulatory mechanism for activation ofeNOS.
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3,530 citations
TL;DR: One way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
Abstract: The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
3,035 citations
"Histone Deacetylase Inhibitors as A..." refers background in this paper
...We found that VPA and TSA change CYP enzyme expression in neuroblastoma cells [135]....
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...Autophagy can also be regulated through the acetylation of transcription factors such as FOXO [74]....
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...CB17-Prkdc, human melanoma samples,mouse melanoma B16-F10-luc MGCD0103, LBH589, TSA [120] STAT3/IL-10 BALB/c and C57BL/6 mice, TCR transgenic mice, HDAC6recombinant mutants / [121] Tumor associated antigens in vitro prostate cancer LNCaP, breast cancer MDA-MB-231 SAHA, entinostat [123] MHC genes in vitro prostate cancer PCa and DU-145 VPA [126]...
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...Co-treatment of several cancer cells (prostate, pancreatic, lung and AML) with TSA and decitabine synergistically induced apoptosis [52,55,145,146]....
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...(I) Whereas trichostatin A (TSA) is an HDAC inhibitor used only in laboratory experiments because of its toxicity, vorinostat (suberoylanilide hydroxamic acid, SAHA) which has been already approved by United States Food and Drug Administration (FDA) as the first HDAC inhibitor, is utilized for the treatment of relapsed and refractory cutaneous T-cell lymphoma (CTCL)....
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TL;DR: Recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors are summarized and how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs are discussed.
Abstract: Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.
2,777 citations
"Histone Deacetylase Inhibitors as A..." refers background in this paper
...HATs catalyze the transfer of an acetyl group from acetyl-CoA to the ε-NH2 group of lysine residues in proteins, while HDACs remove it [12]....
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TL;DR: The genetic findings provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity, suggesting immune-mediated elimination.
2,600 citations
"Histone Deacetylase Inhibitors as A..." refers background in this paper
...Several tumor associated antigens have been shown to be epigenetically silenced in malignancies impede immune recognition by cytotoxic T cells and contributing to worse prognosis [124,125]....
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