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Vorinostat—An Overview Aditya Kumar Bubna

Abstract From the Consultant is a new drug used in the management of cutaneous T cell lymphoma when the Dermatologist, Kedar Hospital, persists, gets worse or comes back during or after treatment with other medicines. It is Chennai, Tamil Nadu, India an efficacious and well tolerated drug and has been considered a novel drug in the treatment of this condition. Currently apart from cutaneous T cell lymphoma the role of Vorinostat for Address for correspondence: other types of cancers is being investigated both as mono-therapy and combination therapy. Dr. Aditya Kumar Bubna, Kedar Hospital, Mugalivakkam Key Words: Cutaneous T cell lymphoma, histone deacytelase inhibitor, Vorinostat Main Road, Porur, Chennai - 600 125, Tamil Nadu, India. E-mail: [email protected]

What was known? • Vorinostat is a inhibitor. • It is an FDA approved drug for the treatment of cutaneous T cell lymphoma.

Introduction of Vorinostat is approximately 9. Vorinostat is slightly Vorinostat is a histone deacetylase (HDAC) inhibitor, soluble in water, alcohol, isopropanol and acetone and is structurally belonging to the hydroxymate group. Other completely soluble in dimethyl sulfoxide. drugs in this group include , , Mechanism of action , and . These Vorinostat is a broad inhibitor of HDAC activity and inhibits are an emergency class of drugs with potential anti- class I and class II HDAC enzymes.[2,3] However, Vorinostat neoplastic activity. These drugs were developed with the does not inhibit HDACs belonging to class III. Based on realization that apart from genetic mutation, alteration crystallographic studies, it has been seen that Vorinostat of HDAC enzymes affected the phenotypic and genotypic binds to the zinc atom of the catalytic site of the HDAC expression in cells, which in turn lead to disturbed enzyme with the phenyl ring of Vorinostat projecting out of homeostasis and neoplastic growth. HDAC inhibitors the catalytic domain onto the surface of the HDAC enzyme.[4] have multiple effects in vivo and in vitro specific for cell On binding to the HDAC enzyme there is accumulation of types, like arresting growth, affecting cell differentiation acetylated proteins including histones, which in turn and bringing about complete of malignant manifests in multiple cellular effects.[5,6] The effects seen cells. These drugs can be used both as mono-therapy and include transcriptional and non-transcriptional.[7,8] in combination with other anti-neoplastic drugs. Despite the proven anti-cancer effects of HDAC inhibitors many Transcriptional effects aspects of its mechanics are not fully clear. This review The transcriptional effects could be by the direct HDAC will help us understand about these drugs in particular binding of Vorinostat or indirectly by acting on various Vorinostat which is an FDA-approved drug for cutaneous transcriptional factors like E2F-1, YY-1, Smad 7, p 53, T-cell lymphoma (CTCL). Bcl-6 and GATA-1. This may result in the alteration in the expression of certain genes. For example, acetylation Chemistry of Bcl-6 transcriptional activator can give rise to an Vorinostat also known as suberoylanilide hydroxamic acid inhibition of transcriptional repression by Bcl-6.[9] Other (SAHA) is an orally bioavailable inhibitor of class I and II indirect transcriptional effects seen with Vorinostat are HDACs. It is a small-molecular-weight linear hydroxamic acetylation of lysine residues of alpha tubulin and heat acid compound, with an empirical formula of C14H20N2O3 shock protein-90. This in turn may lead to decreases and a molecular weight of 264.32 g/mol.[1] The pKa in the activity of pro-growth and pro-survival client Access this article online proteins, such as Bcr-Abl, mutant FLT-3, c-raf and AKT Quick Response Code: in human leukemia cells.[10] Website: www.e‑ijd.org Non-transcriptional effects The non-transcriptional effects of Vorinostat can be divided into: DOI: 10.4103/0019-5154.160511 1. arrest 2. Apoptosis

23 Indian Journal of Dermatology 2015; ??(?) Bubna: Vorinostat

3. Inhibition of angiogenesis administering Vorinostat with food may prevent some 4. Down regulation of immunosuppressive interleukins gastro-intestinal side effects. Vorinostat is metabolized and excreted after glucoronidation by uridine diphosphate Cell cycle arrest glucoronosyl transferase (UGT). Polymorphism in the Vorinostat up regulates cyclin-dependent kinase gene encoding this enzyme system, UGT1A1, maybe an inhibitor p 21 which in turn antagonizes the cyclin/CDK important predictor of Vorinostat toxicity and response complexes leading to cell G1 cycle arrest in malignant levels in individual patients.[26] Similarly certain [11,12] cell lines. Furthermore Vorinostat causes reduced polymorphisms in the thymidylate synthase gene may cyclin-dependant kinase activity via down regulation predict whether Vorinostat will generate an efficacious of cyclins, causing Rb dephosphorylation and indirectly response.[27] Vorinostat is not metabolized by and does [13] affecting E2F transcription activity. not inhibit cytochrome P-450 isoenzyme system and Apoptosis only two drugs, warfarin and sodium , have [28] Vorinostat induces apoptosis in hematological been noted to interact with Vorinostat. malignancies and solid tumors using both transcription- Indications [14,15] and transcription-independent mechanisms. Vorinostat is an FDA-approved drug in the management Inhibition of HDAC changes the balance between pro and of CTCL. Studies have also shown that Vorinostat may anti-apoptotic proteins involved in cell death. Extrinsic inhibit tumor growth by both oral and parenteral apoptotic pathways, death receptors and ligands are in administration in ,[29] leukemia,[30] breast turn up regulated by Vorinostat. Furthermore, tumor cancer,[31] [32] and .[33] necrosis factor-related apoptosis inducing ligand (TRAIL) is restored by Vorinostat in TRAIL-resistant malignant Dosing cells.[16] Along with this Vorinostat down regulates pro- The approved dosage of Vorinostat is 400 mg given survival proteins like Bcl-1 and Bcl-2 which regulate orally once a day.[34] With this dosage a response rate mitochondrial integrity,[17] and up regulate pro-apoptotic of 31% is seen with very few life-threatening adverse proteins such as Bim, Bak and Bax, which function effects. However, if adverse effects become intolerable a as sensors of cellular stress and initiate the intrinsic reduction of the dosage to 300 mg once daily can be pathway.[18] Apart from this, hyperacetylation in warranted. In patients who received Vorinostat 300 mg malignant cells promotes stabilization of p 53[19] which twice daily produced an overall response rate of only is of importance in CTCL lines.[20] 21% with adverse effects like pulmonary embolism and . Vorinostat is supplied as 100 mg Inhibition of angiogenesis capsules approved for oral administration. However, an Vorinostat acts indirectly under hypoxic conditions i.v. formulation has been comparatively analyzed for suppressing hypoxia inducible factor (HIF)-1 alpha and efficacy and safety.[35] Response rates for i.v. Vorinostat vascular endothelial growth factor (VEGF) and thus 300-600 mg/m2 given 5 days a week for 3 weeks were [21,22] blocks angiogenesis. similar to the oral dosing of 400 mg per day. However, Down regulation of immunosuppressive interleukins severe hematologic adverse effects were quite common Vorinostat down regulates interleukin 10(IL-10), an in the patients who received i.v. Vorinostat. Secondly, immunosuppressive interleukin and increases IL-2 and the inconvenience of daily infusion render the oral IL-4 RNA, supporting the fact that Vorinostat acts as a route better suited for CTCL treatment. Prior to starting STAT 3 inhibitor.[23] Vorinostat various other skin directed therapies and cytotoxic therapies ought to be considered in patients Vorinostat is toxic selectively on tumor cells. The with systemic and progressive disease.[36] reason for the selective toxicity of Vorinostat is not fully understood. However, studies have shown that Adverse effects thioredoxin in normal cells may be responsible for Toxicities with Vorinostat were seen when the dosing preventing the insult on the normal cells. Recent studies exceeded 400 mg a day, rendering the clinical benefits have also shown that HR23B is a bio-marker for the of dose escalation very minimal. With the FDA-approved sensitivity of CTCL cells to Vorinostat.[24] dosing the most common side effects encountered include , and nausea. These side effects were usually mild to moderate needing no intervention Vorinostat administered orally in a dose of 200-600 mg or non-invasive intervention. Other side effects that has demonstrated a linear relationship between the were life threatening and required hospitalization [25] [37] plasma concentration and Vorinostat dose. The t1/2 of included thrombocytopenia, dehydration, pulmonary Vorinostat is around 60 to 100 minutes. The absorption embolism, squamous cell carcinoma and severe . and of Vorinostat do not significantly There have also been reports of QTc-interval prolongation differ in the absence or presence of food, although in some patients taking Vorinostat.[38] Therefore, it is

Indian Journal of Dermatology 2015; ??(?) 24 Bubna: Vorinostat advisable that patients who are on anti-arrhythmic drugs 10. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, et al. should undergo a regular screening when on Vorinostat. Inhibition of histone deacetylase 6 acetylates and disrupts the Vorinostat is a category D drug in pregnancy. A study in chaperone function of heat shock protein 90: A novel basis for antileukemia activity of histone deacetylase inhibitors. J animals found that Vorinostat crosses the placenta and Biol Chem 2005;280:26729-34. [39] may harm the developing fetus. The most common 11. Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone developmental defects seen were low fetal birth weight deacetylase inhibitors selectively induces p21WAF1 expression and incomplete ossification of the skull, vertebrae, and and gene-associated histone acetylation. Proc Natl Acad Sci other bones of the axial skeleton. U S A 2000;97:10014-9. 12. Sandor V, Senderowicz A, Mertins S, Sackett D, Future direction Sausville E, Blagosklonny MV, et al. P21-dependant g(1)arrest In addition to its efficacy in CTCL Vorinostat appears with downregulation of cyclin D1 and upregulation of cyclin to have activity in the treatment of other cancers. E by the histone deacetylase inhibitor FR901228. Br J Cancer 2000;83:817-25. Multiple Phase I studies of Vorinostat for various solid 13. Zhao Y, Tan J, Zhuang L, Jiang X, Liu ET, Yu Q. Inhibitors of and hematologic malignancies have shown promise. histone deacetylases target the Rb-E2F1 pathway for apoptosis Studies have shown that Vorinostat had shown to give induction through the activation of proapoptotic protein Bim. a complete response in a patient with diffuse large Proc Nactl Acad Sci U S A 2005;102:16090-5. B-cell lymphoma (DLBCL), with partial responses in 14. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the mesothelioma, laryngeal and thyroid tumors. Currently promise of epigenetic (and more) treatments for cancer. Nat over 90 clinical trials involving Vorinostat are in Rev Cancer 2006;6:38-51. progress. Results from some of these may provide insight 15. Bolden JE, Peart MJ, Johnstone RW. Anti-cancer activities into the efficacy of Vorinostat as monotherapy or as a of histone deacetylase inhibitors. Nat Rev Drug Discov 2006;5:769-84. part of combination therapy in various cancers. 16. Srivastava RK, Kurzrock R, Shankar S. MS-275 sensitizes TRAIL-resistant cells, inhibits angiogenesis and Conclusion metastasis, and reverses epithelial-mesenchymal transistion Vorinostat, a novel HDAC inhibitor, is efficacious and well in vivo. Mol Cancer Ther 2010;9:3254-66. tolerated in patients with CTCL and is being investigated 17. Rikiishi H. Autophagic and apoptotic effects of HDAC inhibitors for its efficacy and safety in other types of cancers as a on cancer cells. J Biomed Biotechnol 2011;2011:830260. part of combination therapy. 18. Zhang Y, Adachi M, Kawamura R, Imai K. Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA- What is new? induced apoptosis. Cell Death Differ 2006;13:129-40. • The efficacy of Vorinostat for prostate cancer, leukemia, breast cancer, glioma 19. Xu Y. Regulation of p53 responses by post-translational and lung cancer has been clearly demonstrated in the recent past. modifications. Cell Death Differ 2003;10:400-3. • At present various phase I trials for other solid and haematologic malignancies have shown promise with Vorinosta. 20. O’Connor OA. Developing new drugs for the treatment of lymphoma. Eur J Haematol Suppl 2005;150-8. 21. Lin EY, Pollard JW. Tumour-associated macrophages press the References angiogenic switch in breast cancer. Cancer Res 2007;67:5064-6. 1. Zolinza (Vorinostat) Full Prescribing Information. White House 22. Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Station, NJ: Merck and Co; 2006. et al. 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Histone deacetylase inhibitors: Potential in Sherrod A, et al. Thymidylate synthase gene polymorphism cancer therapy. J Cell Biochem 2009;107:600-8. determines response and toxicity of 5-FU . 9. Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation inactivates Pharmacogenomics J 2001;1:65-70. the transcriptional repressor BCL6. Nat Genet 2002;32:606-13. 28. Sakajiri S, Kumagai T, Kawamata N, Saitoh T, Said JW,

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Koeffler HP,et al. Histone deacetylase inhibitors profoundly of advanced primary cutaneous T-cell lymphoma. Oncologist decrease proliferation of human lymphoid cancer cell lines. 2007;12:1247-52. Exp Hematol 2005;33:53-61. 35. O’Connor OA, Heaney ML, Schwartz L, Richardson S, 29. Bulter LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon- Willim R, MacGregor-Cortelli B, et al. Clinical experience Cardo C, et al. Suberoylanilide hydroxamic acid, an inhibitor with intravenous and oral formulations of the novel histone of histone deacetylase, suppresses the growth of prostate deacetylase inhibitor suberoylanilide hydroxamic acid in cancer cells in vitro and in vivo. Cancer Res 2000;60:5165-70. patients with advanced hematologic malignancies. J Clin Oncol 30. He LZ, Tolentino T, Grayson P, Zhong S, Warrell RP Jr, 2006;24:166-73. Rifkind RA, et al. Histone deacetylase inhibitors induce 36. Lansigan F, Choi J, Foss FM. Cutaneous T-cell lymphoma. remission in transgenic models of therapy-resistant acute Hematol Oncol Clin North Am 2008;22:979-96, x. promyelocytic leukemia. J Clin Invest 2001;108:1321-30. 37. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al. 31. Cohen LA, Marks PA, Rifkind RA, Amin S, Desai D, Phase II trial of oral vorinostat (suberoylanilide hydroxamic Pittman B, et al. Suberoylanilide hydroxamic acid (SAHA), acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). a histone deacetylase inhibitor, suppresses the growth of Blood 2007;109:31-9. carcinogen-induced mammary tumours. Anticancer Res 38. Vorinostat (Zolinza) for cutaneous T-cell lymphoma. Med Lett 2002;22:1497-504. Drugs Ther 2007;49:23-4. 32. Eyüpoglu IY, Hahnen E, Buslei R, Siebzehnrübl FA, 39. Wise LD, Turner KJ, Kerr JS. Assessment of developmental Savaskan NE, Lüders M, et al. Suberoylanilide hydroxamic acid toxicity of vorinostat, a histone deacetylase inhibitor, in (SAHA) has potent anti-glioma properties in vitro, ex vivo and Sprague-Dawley rats and Dutch Belted rabbits. Birth Defects in vivo. J Neurochem 2005;93:992-9. Res B Dev Reprod Toxicol 2007;80:57-68. 33. Desai D, Das D, Cohen L, el Bayoumy K, Amin S. Chemopreventive efficacy of suberoylanilide hydroxamic acid (SAHA) against 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK)-induced lung tumorigenesis in female A/J How to cite this article: Bubna AK. Vorinostat-An overview. Indian J mice. Anticancer Res 2003;23:499-503. Dermatol 2015;60:419. 34. Mann BS, Johnson JR, Cohen MH, Justice R, Received: January, 2014. Accepted: June, 2014. Pazdur R. FDA approval summary: Vorinostat for treatment Source of support: Nil, Conflict of Interest: Nil.

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