E-IJD RESIDENTS' PAGE Vorinostat—An Overview Aditya Kumar Bubna Abstract From the Consultant Vorinostat is a new drug used in the management of cutaneous T cell lymphoma when the Dermatologist, Kedar Hospital, disease 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 histone deacetylase 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 Givinostat, Abexinostat, Mechanism of action Panobinostat, Belinostat and Trichostatin A. 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 apoptosis 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. Cell cycle 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 valproate, 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 prostate cancer,[29] leukemia,[30] breast turn up regulated by Vorinostat. Furthermore, tumor cancer,[31] glioma[32] and lung cancer.[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 thrombocytopenia. 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 fatigue, diarrhea and nausea. These side effects Pharmacokinetics 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 anemia. and bioavailability 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