Abstract
Histone deacetylases (HDACs) are expressed at increased levels in cells of various malignancies, and the use of HDAC inhibitors has improved outcomes in patients with haematological malignancies (T-cell lymphomas and multiple myeloma). However, they are not as effective in solid tumours. Five agents are currently approved under various jurisdictions, namely belinostat, chidamide, panobinostat, romidepsin and vorinostat. These agents are associated with a range of class-related and agent-specific serious and/or severe adverse effects, notably myelosuppression, diarrhoea and various cardiac effects. Among the cardiac effects are ST-T segment abnormalities and QTc interval prolongation of the electrocardiogram, isolated cases of atrial fibrillation and, in rare instances, ventricular tachyarrhythmias. In order to improve the safety profile of this class of drugs as well as their efficacy in indications already approved and to further widen their indications, a large number of newer HDAC inhibitors with varying degrees of HDAC isoform selectivity have been synthesised and are currently under clinical development. Preliminary evidence from early studies suggests that they may be effective in non-haematological cancers as well when used in combination with other therapeutic modalities, but that they too appear to be associated with the above class-related adverse effects. As the database accumulates, the safety, efficacy and risk/benefit of the newer agents and their indications will become clearer.
Similar content being viewed by others
References
Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017. https://doi.org/10.3390/ijms18071414.
Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. J Cell Physiol. 2000;184:1–16.
Mahlknecht U, Hoelzer D. Histone acetylation modifiers in the pathogenesis of malignant disease. Mol Med. 2000;6:623–44.
Timmermann S, Lehrmann H, Polesskaya A, Harel-Bellan A. Histone acetylation and disease. Cell Mol Life Sci. 2001;58:728–36.
West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124:30–9.
Ceccacci E, Minucci S. Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia. Br J Cancer. 2016;114:605–11.
Imai Y, Maru Y, Tanaka J. Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies. Cancer Sci. 2016;107:1543–9.
Benedetti R, Conte M, Altucci L. Targeting histone deacetylases in diseases: where are we? Antioxid Redox Signal. 2015;23:99–126.
Suraweera A, O’Byrne KJ, Richard DJ. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi. Front Oncol. 2018;8:92.
Lernoux M, Schnekenburger M, Dicato M, Diederich M. Anti-cancer effects of naturally derived compounds targeting histone deacetylase 6-related pathways. Pharmacol Res. 2018;129:337–56.
Hayashi A, Horiuchi A, Kikuchi N, Hayashi T, Fuseya C, Suzuki A, et al. Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin. Int J Cancer. 2010;127:1332–46.
Krämer OH, Göttlicher M, Heinzel T. Histone deacetylase as a therapeutic target. Trends Endocrinol Metab. 2001;12:294–300.
De Souza C, Chatterji BP. HDAC inhibitors as novel anti-cancer therapeutics. Recent Pat Anticancer Drug Discov. 2015;10:145–62.
Goey AK, Sissung TM, Peer CJ, Figg WD. Pharmacogenomics and histone deacetylase inhibitors. Pharmacogenomics. 2016;17:1807–15.
Shi B, Xu W. The development and potential clinical utility of biomarkers for HDAC inhibitors. Drug Discov Ther. 2013;7:129–36.
Food and Drug Administration. Drug-specific reviews on Drugs@FDA. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
European Medicines Agency. Drug-specific assessment reports and labels. Available at: https://www.ema.europa.eu/en/medicines/field_ema_web_categories%253Aname_field/Human/ema_group_types/ema_medicine.
European Medicines Agency. Vorinostat - withdrawal assessment report (EMEA/CHMP/559066/2008). Available at: https://www.ema.europa.eu/documents/withdrawal-report/withdrawal-assessment-report-vorinostat-msd_en.pdf.
European Medicines Agency. Refusal of the marketing authorisation for Istodax (romidepsin) (EMA/475603/2012). Available at: https://www.ema.europa.eu/documents/smop-initial/questions-answers-refusal-marketing-authorisation-istodax-romidepsin_en.pdf.
Ververis K, Hiong A, Karagiannis TC, Licciardi PV. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents. Biologics. 2013;7:47–60.
Moskowitz AJ, Horwitz SM. Targeting histone deacetylases in T-cell lymphoma. Leuk Lymphoma. 2017;58:1306–19.
Ramalingam SS, Kummar S, Sarantopoulos J, Shibata S, LoRusso P, Yerk M, et al. Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. J Clin Oncol. 2010;28:4507–12.
Sharma S, Witteveen PO, Lolkema MP, Hess D, Gelderblom H, Hussain SA, et al. A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and varying degrees of renal function. Cancer Chemother Pharmacol. 2015;75:87–95.
Hamberg P, Woo MM, Chen LC, Verweij J, Porro MG, Zhao L, et al. Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor. Cancer Chemother Pharmacol. 2011;68:805–13.
Yong WP, Ramirez J, Innocenti F, Ratain MJ. Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes. Clin Cancer Res. 2005;11:6699–704.
Wong NS, Seah EZh, Wang LZ, Yeo WL, Yap HL, Chuah B, et al. Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer. Pharmacogenet Genom. 2011;21:760–8.
Goey AK, Figg WD. UGT genotyping in belinostat dosing. Pharmacol Res. 2016;105:22–7.
Dong D, Zhang T, Lu D, Liu J, Wu B. In vitro characterization of belinostat glucuronidation: demonstration of both UGT1A1 and UGT2B7 as the main contributing isozymes. Xenobiotica. 2017;47:277–83.
Food and Drug Administration. Label for FARYDAK (panobinostat) (23 February 2015). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205353s000lbl.pdf.
Agarwal N, McPherson JP, Bailey H, Gupta S, Werner TL, Reddy G, et al. A phase I clinical trial of the effect of belinostat on the pharmacokinetics and pharmacodynamics of warfarin. Cancer Chemother Pharmacol. 2016;77:299–308.
Munster PN, Rubin EH, Van Belle S, Friedman E, Patterson JK, Van Dyck K, et al. A single supratherapeutic dose of vorinostat does not prolong the QTc interval in patients with advanced cancer. Clin Cancer Res. 2009;15:7077–84.
Lynch DR Jr, Washam JB, Newby LK. QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: a case report and review of the literature. Cardiol J. 2012;19:434–8.
Shah MH, Binkley P, Chan K, Xiao J, Arbogast D, Collamore M, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res. 2006;12:3997–4003.
Sager PT, Balser B, Wolfson J, Nichols J, Pilot R, Jones S, et al. Electrocardiographic effects of class 1 selective histone deacetylase inhibitor romidepsin. Cancer Med. 2015;4:1178–85.
Fischer T, Patnaik A, Bhalla K, Beck J, Morganroth J, Laird GH, et al. Results of cardiac monitoring during phase I trials of a novel histone deacetylase (HDAC) inhibitor LBH589 in patients with advanced solid tumors and hematologic malignancies. J Clin Oncol. 2005;23(16_suppl):Abstract 3106.
Shi Y, Dong M, Hong X, Zhang W, Feng J, Zhu J, et al. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol. 2015;26:1766–71.
Schiattarella GG, Sannino A, Toscano E, Cattaneo F, Trimarco B, Esposito G, et al. Cardiovascular effects of histone deacetylase inhibitors epigenetic therapies: systematic review of 62 studies and new hypotheses for future research. Int J Cardiol. 2016;219:396–403.
Dinarello CA, Fossati G, Mascagni P. Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. Mol Med. 2011;17:333–52.
Millard CJ, Watson PJ, Fairall L, Schwabe JWR. Targeting class I histone deacetylases in a “complex” environment. Trends Pharmacol Sci. 2017;38:363–77.
Pang M, Zhuang S. Histone deacetylase: a potential therapeutic target for fibrotic disorders. J Pharmacol Exp Ther. 2010;335:266–72.
Milan M, Pace V, Maiullari F, Chirivì M, Baci D, Maiullari S, et al. Givinostat reduces adverse cardiac remodeling through regulating fibroblasts activation. Cell Death Dis. 2018;9:108.
Gryder BE, Sodji QH, Oyelere AK. Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed. Future Med Chem. 2012;4:505–24.
Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969–78.
Blaheta RA, Cinatl J Jr. Anti-tumor mechanisms of valproate: a novel role for an old drug. Med Res Rev. 2002;22:492–511.
Lagace DC, Nachtigal MW. Inhibition of histone deacetylase activity by valproic acid blocks adipogenesis. J Biol Chem. 2004;279:18851–60.
Chateauvieux S, Morceau F, Dicato M, Diederich M. Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010;2010:479364. https://doi.org/10.1155/2010/479364.
Eikel D, Lampen A, Nau H. Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives. Chem Res Toxicol. 2006;19:272–8.
Shah RR, Stonier PD. Repurposing old drugs in oncology: opportunities with clinical and regulatory challenges ahead. J Clin Pharm Ther. 2018. https://doi.org/10.1111/jcpt.12759.
Evens AM, Balasubramanian S, Vose JM, Harb W, Gordon LI, Langdon R, et al. A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma. Clin Cancer Res. 2016;22:1059–66.
Vey N, Prebet T, Thalamas C, Charbonnier A, Rey J, Kloos I, et al. Phase 1 dose-escalation study of oral abexinostat for the treatment of patients with relapsed/refractory higher-risk myelodysplastic syndromes, acute myeloid leukemia, or acute lymphoblastic leukemia. Leuk Lymphoma. 2017;58:1880–6.
Ribrag V, Kim WS, Bouabdallah R, Lim ST, Coiffier B, Illes A, et al. Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II study. Haematologica. 2017;102:903–9.
Kim KP, Park SJ, Kim JE, Hong YS, Lee JL, Bae KS, et al. First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies. Invest New Drugs. 2015;33:1048–57.
Prebet T, Sun Z, Figueroa ME, Ketterling R, Melnick A, Greenberg PL, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J Clin Oncol. 2014;32:1242–8.
Galli M, Salmoiraghi S, Golay J, Gozzini A, Crippa C, Pescosta N, et al. A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma. Ann Hematol. 2010;89:185–90.
Younes A, Berdeja JG, Patel MR, Flinn I, Gerecitano JF, Neelapu SS, et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2016;17:622–31.
Boumber Y, Younes A, Garcia-Manero G. Mocetinostat (MGCD0103): a review of an isotype-specific histone deacetylase inhibitor. Expert Opin Investig Drugs. 2011;20:823–9.
Batlevi CL, Crump M, Andreadis C, Rizzieri D, Assouline SE, Fox S, et al. A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma. Br J Haematol. 2017;178:434–41.
Garcia-Manero G, Montalban-Bravo G, Berdeja JG, Abaza Y, Jabbour E, Essell J, et al. Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes. Cancer. 2017;123:994–1002.
Abaza YM, Kadia TM, Jabbour EJ, Konopleva MY, Borthakur G, Ferrajoli A, et al. Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies. Cancer. 2017;123:4851–9.
Venugopal B, Baird R, Kristeleit RS, Plummer R, Cowan R, Stewart A, et al. A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors. Clin Cancer Res. 2013;19:4262–72.
Brunetto AT, Ang JE, Lal R, Olmos D, Molife LR, Kristeleit R, et al. First-in-human, pharmacokinetic and pharmacodynamic phase I study of resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2013;19:5494–504.
Kitazono S, Fujiwara Y, Nakamichi S, Mizugaki H, Nokihara H, Yamamoto N, et al. A phase I study of resminostat in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2015;75:1155–61.
Vogl DT, Raje N, Jagannath S, Richardson P, Hari P, Orlowski R, et al. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin Cancer Res. 2017;23:3307–15.
Shultz MD, Cao X, Chen CH, Cho YS, Davis NR, Eckman J, et al. Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors. J Med Chem. 2011;54:4752–72.
Spence S, Deurinck M, Ju H, Traebert M, McLean L, Marlowe J, et al. Histone deacetylase inhibitors prolong cardiac repolarization through transcriptional mechanisms. Toxicol Sci. 2016;153:39–54.
Kopljar I, Gallacher DJ, De Bondt A, Cougnaud L, Vlaminckx E, Van den Wyngaert I, et al. Functional and transcriptional characterization of histone deacetylase inhibitor-mediated cardiac adverse effects in human induced pluripotent stem cell-derived cardiomyocytes. Stem Cells Transl Med. 2016;5:602–12.
Li P, Kurata Y, Endang M, Ninomiya H, Higaki K, Taufiq F, et al. Restoration of mutant hERG stability by inhibition of HDAC6. J Mol Cell Cardiol. 2018;115:158–69.
Kazim S, Mohindra R, Gosselin S, Larocque A. QTc prolongation and valproate toxicity. Clin Toxicol (Phila). 2013;51:193.
Shadnia S, Amiri H, Hassanian-Moghaddam H, Rezai M, Vasei Z, Ghodrati N, et al. Favorable results after conservative management of 316 valproate intoxicated patients. J Res Med Sci. 2015;20:656–61.
Acciavatti T, Martinotti G, Corbo M, Cinosi E, Lupi M, Ricci F, et al. Psychotropic drugs and ventricular repolarisation: the effects on QT interval, T-peak to T-end interval and QT dispersion. J Psychopharmacol. 2017;31:453–60.
Subramanian S, Bates SE, Wright JJ, Espinoza-Delgado I, Piekarz RL. Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals (Basel). 2010;3:2751–67.
Gentile S. Risks of neurobehavioral teratogenicity associated with prenatal exposure to valproate monotherapy: a systematic review with regulatory repercussions. CNS Spectr. 2014;19:305–15.
Tomson T, Marson A, Boon P, Canevini MP, Covanis A, Gaily E, et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 2015;56:1006–19.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
This is a review of the data in the public domain and the author declares compliance with all ethical standards.
Funding
No sources of funding were used to assist in the preparation of this review.
Conflict of interest
Rashmi Shah has no conflicts of interest that are relevant to the content of this review and has not received any financial support for writing it. He was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK, and now provides expert consultancy services to a number of pharmaceutical companies.
Additional information
Part of a theme issue on “Safety of Novel Anticancer Therapies: Future Perspectives”. Guest Editors: Rashmi R. Shah, Giuseppe Curigliano.
Rights and permissions
About this article
Cite this article
Shah, R.R. Safety and Tolerability of Histone Deacetylase (HDAC) Inhibitors in Oncology. Drug Saf 42, 235–245 (2019). https://doi.org/10.1007/s40264-018-0773-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40264-018-0773-9