   |
|
E-IJD-RESIDENTS' PAGE |
|
| Year : 2015 | Volume
: 60
| Issue : 4 | Page : 419 |
|
| Vorinostat-An overview |
|
|
Aditya Kumar Bubna
Consultant Dermatologist, Kedar Hospital, Chennai, Tamil Nadu, India
| Date of Web Publication | 10-Jul-2015 |
Correspondence Address:
Dr. Aditya Kumar Bubna
Kedar Hospital, Mugalivakkam Main Road, Porur, Chennai - 600 125, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0019-5154.160511
|
|
 Abstract | | |
Vorinostat is a new drug used in the management of cutaneous T cell lymphoma when the disease persists, gets worse or comes back during or after treatment with other medicines. It is 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 other types of cancers is being investigated both as mono-therapy and combination therapy.
Keywords: Cutaneous T cell lymphoma, histone deacytelase inhibitor, Vorinostat
How to cite this article:
Bubna AK. Vorinostat-An overview. Indian J Dermatol 2015;60:419 |
What was known?
- Vorinostat is a histone deacetylase inhibitor.
- It is an FDA approved drug for the treatment of cutaneous T cell lymphoma.
| Introduction | |  |
Vorinostat is a histone deacetylase (HDAC) inhibitor, structurally belonging to the hydroxymate group. Other drugs in this group include Givinostat, Abexinostat, Panobinostat, Belinostat and Trichostatin A. These are an emergency class of drugs with potential anti-neoplastic activity. These drugs were developed with the realization that apart from genetic mutation, alteration of HDAC enzymes affected the phenotypic and genotypic expression in cells, which in turn lead to disturbed homeostasis and neoplastic growth. HDAC inhibitors have multiple effects in vivo and in vitro specific for cell types, like arresting growth, affecting cell differentiation and bringing about complete apoptosis of malignant cells. These drugs can be used both as mono-therapy and in combination with other anti-neoplastic drugs. Despite the proven anti-cancer effects of HDAC inhibitors many aspects of its mechanics are not fully clear. This review will help us understand about these drugs in particular Vorinostat which is an FDA-approved drug for cutaneous T-cell lymphoma (CTCL).
Chemistry
Vorinostat also known as suberoylanilide hydroxamic acid (SAHA) is an orally bioavailable inhibitor of class I and II HDACs. It is a small-molecular-weight linear hydroxamic acid compound, with an empirical formula of C 14 H 20 N 2 O 3 and a molecular weight of 264.32 g/mol. [1] The pKa of Vorinostat is approximately 9. Vorinostat is slightly soluble in water, alcohol, isopropanol and acetone and is completely soluble in dimethyl sulfoxide.
Mechanism of action
Vorinostat is a broad inhibitor of HDAC activity and inhibits class I and class II HDAC enzymes. [2],[3] However, Vorinostat does not inhibit HDACs belonging to class III. Based on crystallographic studies, it has been seen that Vorinostat binds to the zinc atom of the catalytic site of the HDAC enzyme with the phenyl ring of Vorinostat projecting out of the catalytic domain onto the surface of the HDAC enzyme. [4] On binding to the HDAC enzyme there is accumulation of acetylated proteins including histones, which in turn manifests in multiple cellular effects. [5],[6] The effects seen include transcriptional and non-transcriptional. [7],[8]
Transcriptional effects
The transcriptional effects could be by the direct HDAC binding of Vorinostat or indirectly by acting on various transcriptional factors like E2F-1, YY-1, Smad 7, p 53, Bcl-6 and GATA-1. This may result in the alteration in the expression of certain genes. For example, acetylation of Bcl-6 transcriptional activator can give rise to an inhibition of transcriptional repression by Bcl-6. [9] Other indirect transcriptional effects seen with Vorinostat are acetylation of lysine residues of alpha tubulin and heat shock protein-90. This in turn may lead to decreases in the activity of pro-growth and pro-survival client proteins, such as Bcr-Abl, mutant FLT-3, c-raf and AKT in human leukemia cells. [10]
Non-transcriptional effects
The non-transcriptional effects of Vorinostat can be divided into:
- Cell cycle arrest
- Apoptosis
- Inhibition of angiogenesis
- Down regulation of immunosuppressive interleukins
Cell cycle arrest
Vorinostat up regulates cyclin-dependent kinase inhibitor p 21 which in turn antagonizes the cyclin/CDK complexes leading to cell G1 cycle arrest in malignant cell lines. [11],[12] Furthermore Vorinostat causes reduced cyclin-dependant kinase activity via down regulation of cyclins, causing Rb dephosphorylation and indirectly affecting E2F transcription activity. [13]
Apoptosis
Vorinostat induces apoptosis in hematological malignancies and solid tumors using both transcription- and transcription-independent mechanisms. [14],[15] Inhibition of HDAC changes the balance between pro and anti-apoptotic proteins involved in cell death. Extrinsic apoptotic pathways, death receptors and ligands are in turn up regulated by Vorinostat. Furthermore, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is restored by Vorinostat in TRAIL-resistant malignant cells. [16] Along with this Vorinostat down regulates pro-survival proteins like Bcl-1 and Bcl-2 which regulate mitochondrial integrity, [17] and up regulate pro-apoptotic proteins such as Bim, Bak and Bax, which function as sensors of cellular stress and initiate the intrinsic pathway. [18] Apart from this, hyperacetylation in malignant cells promotes stabilization of p 53 [19] which is of importance in CTCL lines. [20]
Inhibition of angiogenesis
Vorinostat acts indirectly under hypoxic conditions suppressing hypoxia inducible factor (HIF)-1 alpha and vascular endothelial growth factor (VEGF) and thus blocks angiogenesis. [21],[22]
Down regulation of immunosuppressive interleukins
Vorinostat down regulates interleukin 10(IL-10), an immunosuppressive interleukin and increases IL-2 and IL-4 RNA, supporting the fact that Vorinostat acts as a STAT 3 inhibitor. [23]
Vorinostat is toxic selectively on tumor cells. The reason for the selective toxicity of Vorinostat is not fully understood. However, studies have shown that thioredoxin in normal cells may be responsible for preventing the insult on the normal cells. Recent studies have also shown that HR23B is a bio-marker for the sensitivity of CTCL cells to Vorinostat. [24]
Pharmacokinetics
Vorinostat administered orally in a dose of 200-600 mg has demonstrated a linear relationship between the plasma concentration and Vorinostat dose. [25] The t 1/2 of Vorinostat is around 60 to 100 minutes. The absorption and bioavailability of Vorinostat do not significantly differ in the absence or presence of food, although administering Vorinostat with food may prevent some gastro-intestinal side effects. Vorinostat is metabolized and excreted after glucoronidation by uridine diphosphate glucoronosyl transferase (UGT). Polymorphism in the gene encoding this enzyme system, UGT1A1, maybe an important predictor of Vorinostat toxicity and response levels in individual patients. [26] Similarly certain polymorphisms in the thymidylate synthase gene may predict whether Vorinostat will generate an efficacious response. [27] Vorinostat is not metabolized by and does not inhibit cytochrome P-450 isoenzyme system and only two drugs, warfarin and sodium valproate, have been noted to interact with Vorinostat. [28]
Indications
Vorinostat is an FDA-approved drug in the management of CTCL. Studies have also shown that Vorinostat may inhibit tumor growth by both oral and parenteral administration in prostate cancer, [29] leukemia, [30] breast cancer, [31] glioma [32] and lung cancer. [33]
Dosing
The approved dosage of Vorinostat is 400 mg given orally once a day. [34] With this dosage a response rate of 31% is seen with very few life-threatening adverse effects. However, if adverse effects become intolerable a reduction of the dosage to 300 mg once daily can be warranted. In patients who received Vorinostat 300 mg twice daily produced an overall response rate of only 21% with adverse effects like pulmonary embolism and thrombocytopenia. Vorinostat is supplied as 100 mg capsules approved for oral administration. However, an i.v. formulation has been comparatively analyzed for efficacy and safety. [35] Response rates for i.v. Vorinostat 300-600 mg/m 2 given 5 days a week for 3 weeks were similar to the oral dosing of 400 mg per day. However, severe hematologic adverse effects were quite common in the patients who received i.v. Vorinostat. Secondly, the inconvenience of daily infusion render the oral route better suited for CTCL treatment. Prior to starting Vorinostat various other skin directed therapies and cytotoxic therapies ought to be considered in patients with systemic and progressive disease. [36]
Adverse effects
Toxicities with Vorinostat were seen when the dosing exceeded 400 mg a day, rendering the clinical benefits of dose escalation very minimal. With the FDA-approved dosing the most common side effects encountered include fatigue, diarrhea and nausea. These side effects were usually mild to moderate needing no intervention or non-invasive intervention. Other side effects that were life threatening and required hospitalization included thrombocytopenia, dehydration, [37] pulmonary embolism, squamous cell carcinoma and severe anemia. There have also been reports of QTc-interval prolongation in some patients taking Vorinostat. [38] Therefore, it is advisable that patients who are on anti-arrhythmic drugs should undergo a regular screening when on Vorinostat. Vorinostat is a category D drug in pregnancy. A study in animals found that Vorinostat crosses the placenta and may harm the developing fetus. [39] The most common developmental defects seen were low fetal birth weight and incomplete ossification of the skull, vertebrae, and other bones of the axial skeleton.
Future direction
In addition to its efficacy in CTCL Vorinostat appears to have activity in the treatment of other cancers. Multiple Phase I studies of Vorinostat for various solid and hematologic malignancies have shown promise. Studies have shown that Vorinostat had shown to give a complete response in a patient with diffuse large B-cell lymphoma (DLBCL), with partial responses in mesothelioma, laryngeal and thyroid tumors. Currently over 90 clinical trials involving Vorinostat are in progress. Results from some of these may provide insight into the efficacy of Vorinostat as monotherapy or as a part of combination therapy in various cancers.
| Conclusion | | |
Vorinostat, a novel HDAC inhibitor, is efficacious and well tolerated in patients with CTCL and is being investigated for its efficacy and safety in other types of cancers as a part of combination therapy.
| References | | |
| 1. | Zolinza (Vorinostat) Full Prescribing Information. White House Station, NJ: Merck and Co; 2006.  |
| 2. | Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: Causes and therapies. Nat Rev Cancer 2001;1:194-202. |
| 3. | Marks PA, Dokmanovic M. Histone deacetylase inhibitors: Discovery and development as anticancer agents. Expert Opin Investig Drugs 2005;14:1497-511. |
| 4. | Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 1999;401:188-93. |
| 5. | Johnstone RW, Licht JD. Histone deacetylase inhibitors in cancer therapy: Is transcription the primary target? Cancer Cell 2003;4:13-8. |
| 6. | Secrist JP, Zhou X, Richon VM. HDAC inhibitors for the treatment of cancer. Curr Opin Investig Drugs 2003;4:1422-7. |
| 7. | Marks PA. Histone deacetylase inhibitors: A chemical genetics approach to understanding cellular functions. Biochem Biophys Acta 2010;1799:717-25. |
| 8. | Marks PA, Xu WS. Histone deacetylase inhibitors: Potential in cancer therapy. J Cell Biochem 2009;107:600-8. |
| 9. | Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation inactivates the transcriptional repressor BCL6. Nat Genet 2002;32:606-13. |
| 10. | Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: A novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 2005;280:26729-34. |
| 11. | Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitors selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A 2000;97:10014-9. |
| 12. | Sandor V, Senderowicz A, Mertins S, Sackett D, Sausville E, Blagosklonny MV, et al. P21-dependant g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br J Cancer 2000;83:817-25. |
| 13. | Zhao Y, Tan J, Zhuang L, Jiang X, Liu ET, Yu Q. Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through the activation of proapoptotic protein Bim. Proc Nactl Acad Sci U S A 2005;102:16090-5. |
| 14. | Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006;6:38-51. |
| 15. | Bolden JE, Peart MJ, Johnstone RW. Anti-cancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006;5:769-84. |
| 16. | Srivastava RK, Kurzrock R, Shankar S. MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transistion in vivo. Mol Cancer Ther 2010;9:3254-66. |
| 17. | Rikiishi H. Autophagic and apoptotic effects of HDAC inhibitors on cancer cells. J Biomed Biotechnol 2011;2011:830260. |
| 18. | Zhang Y, Adachi M, Kawamura R, Imai K. Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ 2006;13:129-40. |
| 19. | Xu Y. Regulation of p53 responses by post-translational modifications. Cell Death Differ 2003;10:400-3. |
| 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 angiogenic switch in breast cancer. Cancer Res 2007;67:5064-6. |
| 22. | Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, et al. Histone deacetylases induce angiogenesis by negative regulation of tumour suppressor genes. Nat Med 2001;7:437-43. |
| 23. | Tiffon C, Adams J, van der Fits L, Wen S, Townsend P, Ganesan A, et al. The histone deacetylase inhibitors vorinostat and romidespin downmodulate IL-10 expression in cutaneous T-cell lymphoma cells. Br J Pharmacol 2011;162:1590-602. |
| 24. | Khan O, Fotheringham S, Wood V, Stimson L, Zhang C, Pezzella F, et al. HR23B is a biomarker for tumour sensitivity to HDAC inhibitor-based therapy. Proc Natl Acad Sci U S A 2010;107:6532-7. |
| 25. | Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005;23:3923-31. |
| 26. | Perera MA, Innocenti F, Ratain MJ. Pharmacogenetic testing for uridine diphosphate glucoronosyltransferase 1A1 polymorphisms: Are we there yet? Pharmacotherapy 2008;28:755-68. |
| 27. | Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 2001;1:65-70. |
| 28. | Sakajiri S, Kumagai T, Kawamata N, Saitoh T, Said JW, Koeffler HP, et al. Histone deacetylase inhibitors profoundly decrease proliferation of human lymphoid cancer cell lines. Exp Hematol 2005;33:53-61. |
| 29. | Bulter LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, et al. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 2000;60:5165-70. |
| 30. | He LZ, Tolentino T, Grayson P, Zhong S, Warrell RP Jr, Rifkind RA, et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 2001;108:1321-30. |
| 31. | Cohen LA, Marks PA, Rifkind RA, Amin S, Desai D, Pittman B, et al. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, suppresses the growth of carcinogen-induced mammary tumours. Anticancer Res 2002;22:1497-504. |
| 32. | Eyüpoglu IY, Hahnen E, Buslei R, Siebzehnrübl FA, Savaskan NE, Lüders M, et al. Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo. J Neurochem 2005;93:992-9. |
| 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 mice. Anticancer Res 2003;23:499-503. |
| 34. | Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007;12:1247-52. |
| 35. | O'Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli B, et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 2006;24:166-73. |
| 36. | Lansigan F, Choi J, Foss FM. Cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 2008;22:979-96, x. |
| 37. | Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007;109:31-9. |
| 38. | Vorinostat (Zolinza) for cutaneous T-cell lymphoma. Med Lett Drugs Ther 2007;49:23-4. |
| 39. | Wise LD, Turner KJ, Kerr JS. Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. Birth Defects Res B Dev Reprod Toxicol 2007;80:57-68. |
What is new?
- The efficacy of Vorinostat for prostate cancer, leukemia, breast cancer, glioma and lung cancer has been clearly demonstrated in the recent past.
- At present various phase I trials for other solid and haematologic malignancies have shown promise with Vorinosta.
|
|
|
|
|
|
|
|
|
|
|
|
|
| Article Access Statistics | | | Viewed | 4226 | | | Printed | 48 | | | Emailed | 1 | | | PDF Downloaded | 167 | | | Comments | [Add] | | |
|
|
