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Histone deacetylase inhibitors in cancer therapy

During the last few decades, several approaches have been applied in effort to discover new more effective anticancer drugs. As a result, many promising compounds have been investigated. However, chemoresistance that may arise during chemotherapy is one of the main causes of failure of treatment. To achieve the most efficient treatment, drugs are often used in various combinations. Epigenetic changes are the changes of gene expression or cellular phenotype caused by mechanisms other than the changes of DNA sequence. They include changes of DNA methylation and chromatin remodeling, RNA transcripts and their encoded proteins, expression of non-coding RNAs, posttranslational changes in chromatin and mRNA regulation. Among them, histone acetylation and deacetylation have been investigated as therapeutic targets because of their importance in regulation of gene expression. Changes in histone acetylation influence chromatin condensation and these alterations influence gene transcription (Kim HJ; Bae SC Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am. J. Transl. Res., 2011, 3(2),166-179). The balance between histone transacetylases and deacetylases is often damaged in cancer leading to changed expressions of tumor suppressor genes and/or proto-oncogenes (Kim HJ; Bae SC Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am. J. Transl. Res., 2011, 3(2),166-179, Marks PA, Richon VM, Miller T, Kelly WK. (2004). Histone deacetylase inhibitors.Adv Cancer Res 91: 137–168).

Enzymes Catalyzing Histone Acetylation and Deacetylation

Modification of histones by acetylation affects transcription by changing the structure of chromatin that modulates the accessibility of transcription factors to their target DNA and plays important role in regulation of an expression (Roth SY, Allis CD. Histone acetylation and chromatin assembly: a single escort, multiple dances? Cell 1996;87:5–8, Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403: 41-5). Additionally, acetylation and/or deacetylation of non-histone proteins modify many important cell functions (Spange S, Wagner T, Heinzel T, Krämer OH. Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol 2009;41:185-98). The acetylation state of histones and other proteins is maintained by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. HATs catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues in proteins and HDAC removes it (Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5: 769–84). Depending on mechanisms of removing the acetyl group, HDACs can be dividing into two distinct families. The “classical family” comprises Zn2+-dependent HDACs, the second family of HDACs depends in their catalysis on NAD+ and subsequently, O-acetyl-ADP-ribose and nicotinamide are formed as a result of the acetyl transfer (Trapp J, Jung M. The role of NAD+ dependent histone deacetylases (sirtuins) in ageing.Curr Drug Targets 2006; 7: 1553-60). Furthermore, based on the homology to their yeast analogues, HDACs are divided into four classes. Class I, located in the nucleus, includes HDACs 1, 2, 3 and 8. HDACs 4, 5, 7 and 9 are members of class IIa, while isoforms 6 and 10 that are located both in the cytoplasm and nucleus are classified as class IIb of HDACs. Class IV, which exhibits features of class I and II, includes only HDAC11 [32]. NAD+-dependent homologues 1-7 of the yeast Sir2 proteins (sirtuins) are designed as class III of HDACs, and have mono-ADP-ribosyltransferase activity. HATs, “functional opponents” of HDACs, are divided into Gcn5/PCAF N-acetyltransferases (GNATs) and MYST HATs. Although these two groups of HATs are the major enzymes catalyzing N-acetyltransferase activity, other proteins also exhibit this acetylase activity (Lee KK, Workman JL. Histone acetyltransferase complexes: one size doesn't fit all. Nat Rev Mol Cell Biol 2007; 8: 284-95).

Histone Deacetylases and Cancer
HDACs levels as class I and II vary in different cancer cells. HDAC1 is overexpressed in prostate and gastric cancers, where it signalizes worse prognosis, as well as in lung, esophageal, colon and breast cancers (Halkidou K; Gaughan L; Cook S; Leung HY; Neal DE; Robson CN. Upregulation and nuclear recruitment of HDACI in hormone refraktory prostate cancer. Prostate, 2004, 59(2), 177-189, Choi JH; Kwon HJ; Yoon BI; Kim JH; Han SU; Joo HJ; Kim DY.Expression profile of histone deacetylase 1 in gastric cancer tissues. Jpn. J.Cancer Res., 2001, 92(12), 1300-4. Zhang Z; Yamashita H; Toyama T; Sugiura H; Ando Y; Mita K; Hamaguchi M; Hara Y; Kobayashi S; Iwase H. Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast. Breast Cancer Res.Treat., 2005, 94(1), 11-16). High levels of HDAC2 were found in colorectal, cervical and gastric cancers (Song J; Noh JH; Lee JH; Eun JW; Ahn YM; Kim SY; Lee SH; Park WS; Yoo NJ; Lee JY; Nam SW. Increased expression of historic deacetylase 2 is found in human gastric cancer. Apmis, 2005, 113(4), 264-268, Zhu P; Martin E; Mengwasser J; Schlag P; Janssen KP; Gottlicher M. Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell, 2004, 5(5), 455-463). In addition, HDAC3 is overexpressed in gastric, prostate and colorectal cancer (Wilson AJ; Byun DS; Popova N; Murray LB; L'Italien K; Sowa Y; Arango D; Velcich A; Augenlicht LH; Mariadason JM. Histone deacetylase 3 (HDAC3) and other class IHDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J. Biol. Chem., 2006, 281(19), 13548-58), and high expression of HDAC1 and 2 correlates with reduced patient survival in colorectal carcinomas (Weichert W, Röske A, Niesporek S, Noske A, Buckendahl AC, Dietel M, Gekeler V, Boehm M, Beckers T, Denkert C. Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo. Clin Cancer Res. 2008;14(6):1669-77, Krishnan M, Singh AB, Smith JJ, Sharma A, Chen X, Eschrich S, Yeatman TJ, Beauchamp RD, Dhawan P. HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability. Oncogene. 2010;29(2):305-12). HDAC6 is highly expressed in breast cancer, HDAC8 is over-expressed in neuroblastoma cells and its overexpression correlates with metastasizing and advanced stage of disease with poor prognosis. Expression of HDAC11 is increased in rhabdomyosarcoma (Bolden JE; Peart MJ; Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov., 2006, 5, 769-84, Nakagawa M; Oda Y; Eguchi T; Aishima SI; Yao T; Hosoi F; Basakv Y; Ono M; Kuwano M; Tanaka M; Tsuneyoshi M. Expression profile of class I histone deacetylases in human cancer tissues. Oncol. Rep., 2007, 18(4), 769-74, Oehme I; Deubzer HE; Wegener D; Pickert D; Linke JP; Hero B; KoppSchneider A; Westermann F; Ulrich SM; von Deimling A; Fischer M; Witt O. Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin. Cancer Res., 2009, 15(1), 91-9). miR-449 that target HDAC1 was identified in prostate cancer (Noonan EJ, Place RF, Pookot D, Basak S, Whitson JM, Hirata H, Giardina C, Dahiya R. miR-449a targets HDAC-1 and induces growth arrest in prostate cancer.Oncogene. 2009;28(14):1714-24) and in hepatocellular carcinoma low levels of miR-22, which targets HDAC4, were correlated with worse prognosis (Zhang J, Yang Y, Yang T, Liu Y, Li A, Fu S, Wu M, Pan Z, Zhou W. microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer. 2010;103(8):1215-20). Both diffuse large B-cell lymphomas (DLBCL) and peripheral T-cell lymphomas exhibit HDAC1, 2 and 6 overexpression (Marquard L, Poulsen CB, Gjerdrum LM, de Nully Brown P, Christensen IJ, Jensen PB, Sehested M, Johansen P, Ralfkiaer E. Histone deacetylase 1, 2, 6 and acetylated histone H4 in B- and T-cell lymphomas. Histopathology. 2009;54(6):688-98), whereas Hodgkin's lymphomas display increased HDAC1, 2 and 3 levels (Adams H, Fritzsche FR, Dirnhofer S, Kristiansen G, Tzankov A. Class I histone deacetylases 1, 2 and 3 are highly expressed in classical Hodgkin's lymphoma.Expert Opin Ther Targets. 2010;14(6):577-84). In Waldenstrom macroglobulinemia, the upregulation of miR-9* results in HDAC4 and 5 dowregulation (Roccaro AM, Sacco A, Jia X, Azab AK, Maiso P, Ngo HT, Azab F, Runnels J, Quang P, Ghobrial IM. microRNA-dependent modulation of histone acetylation in Waldenstrom macroglobulinemia. Blood. 2010;116(9):1506-14). Class III of HDACs plays important roles in carcinogenesis. Some of them act as antioncogenes while others influence tumors by controlling the cell metabolism (McGuinness D; McGuinness DH; McCaul JA; Shiels PG. Sirtuins, bioageing, and cancer. J. Aging Res., 2011, 2011:235754). Decreased activities of HDACs are associated with suppressed tumor cell development and growth (Zupkovitz G; Tischler J; Posch M; Sadzak I; Ramsauer K; Egger G; Grausenburger R; Schweifer N; Chiocca S; Decker T; Seiser C. Negative and positive regulation of gene expression by mouse histone deacetylase 1. Mol. Cell. Biol., 2006, 26(21), 7913-28, Montgomery RL; Davis CA; Potthoff MJ; Haberland M; Fielitz J; Qi XX; Hill JA; Richardson JA; Olson EN. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev., 2007, 21(14), 1790-1802). Moreover there have been identi?ed mutations of HDAC4 in breast cancer samples (Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science 2006;314(5797):268-74) and mutation of HDAC2 that caused protein truncation was found in human epithelial cancer cell lines (Ropero S, Fraga MF, Ballestar E, Hamelin R, Yamamoto H, Boix-Chornet M, Caballero R, Alaminos M, Setien F, Paz MF, Herranz M, Palacios J, Arango D, Orntoft TF, Aaltonen LA, Schwartz S Jr, Esteller M. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nat Genet. 2006;38(5):566-9)

Histone Deacetylase inhibitors
The results found in various studies indicate that HDAC inhibitors increase the anticancer efficacy of additional therapy modalities and they therefore would be very efficient in the clinic, in their utilization together with other anticancer therapy modalities including ionizing radiation and/or chemotherapy. Therefore, investigation of the clinical application of HDAC inhibitors has increased with over 490 clinical trials for cancer and with a few for other diseases (B E Gryder, Q H Sodji, A K Oyelere Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeedFuture Med Chem. 2012 ; 4(4):505- 524). Namely, HDAC inhibitors have also be found to be effective for treatment of other diseases. Some HDAC inhibitors have antimalarial properties and are studied as new possible drugs for treatment of malaria (Andrews KT, Tran TN, Fairlie DP Towards histone deacetylase inhibitors as new antimalarial drugs. Curr Pharm Des. 2012;18(24):3467-79). There is also some evidence that HDAC pan-inhibitors and HDAC III inhibitors possess anti-inflammatory effects in models of asthma (Royce SG, Ververis K, Karagiannis TC. Histone deacetylase inhibitors: can we consider potent anti-neoplastic agents for the treatment of asthma? Ann Clin Lab Sci. 2012;42(3):338-45). Here, we describe HDAC inhibitors and mechanisms of their actions, and discuss combination therapies with anti-tumor drugs. HDAC inhibitors may be both specific against only some HDACs (HDAC isoform-selective inhibitors) or against all types of HDACs (pan-inhibitors). They can be classified according to their chemical structure into four groups: 1) hydroxamic acids; 2) aliphatic acids; 2) benzamides; 4) cyclic tetrapeptides (for overview see Kim HJ, Bae SC. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res, 2011; 3(2):166-179). 1) Hydroxamic acids trichostatin A (TSA), vorinostat (suberoylanilide hydroxamic acid, SAHA) which was approved by FDA as the first HDAC inhibitor for the treatment of relapsed and refractory cutaneous T-cell lymphoma (CTCL) (Duvic M, Talpur R, Ni X, Zhang CL, Hazarika P, Kelly C, Chiao JH, Reilly JF, Ricker JL, Richon VM, Frankel SR. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refraktory cutaneous T-cell lymphoma, (CTCL). Blood, 2007, 109(1), 31-39), belinostat (PXD-101) and panobinostat (LBH589) are pan-HDAC inhibitors. 2) The aliphatic acids [valproic acid (VPA), butyric acid and phenylbutyric acid] are only weak inhibitors of HDAC I and IIa (Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene, 2007, 26(37), 5541-52). 3) Benzamides that include entinostat (SNDX-275, MS-275) and mocetinostat (MGCD0103) are isoform selective inhibitors of HDAC I and mocetinostat inhibits also IV HDAC (Dell'Aversana C, Lepore I, Altucci L. HDAC modulation and cell death in the clinic. Exp Cell Res. 2012;318(11):1229-44). 4) The cyclic tetrapeptides, inhibitors of class I HDACs (romidepsin inhibits also HDAC 4 and 6), are cyclic hydroxamic acids containing peptides: romidepsin (depsipeptide, FK228, FR901228), apicidin and trapoxinand. Among them, romidepsin that was approved by the FDA and the EuMedicines Agency to treat CTCL and peripheral T cell lymphomas, is most effective (Campas-Moya C. Romidepsin for the treatment of cutaneous T-cell lymphoma. Drugs Today, 2009, 45(11), 787-795). It is a prodrug, which is activated to a metabolite that chelate the zinc ions in the active center of the HDAC of class I (Furumai R, Matsuyama A, Kobashi N, Lee KH, Nishiyama N, Nakajima I, Tanaka A, Komatsu Y, Nishino N, Yoshida M, Horinouchi S. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res., 2002, 62(17), 4916-4921).

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