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VORINOSTAT: THE FAMOUS HYDROXAMIC ACID

SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) OR VORINOSTAT: 
Functions of HDACi (HDAC inhibitors) is to regulate the gene expression, induction of cell cycle arrest, stimulate apoptosis in cancer cells and modulation of various pathways in tumor cells for example cell proliferation, by hyperacetylating the histone proteins. Due to possessing these abilities, HDAC inhibitors are being used as a very valuable chemotherapeutic anti-cancer agents and SAHA or Vorinostat SAHA is important among them [1]. Vorinostat has found to be possessing strong anti-cancer properties [2] and Vorinostat structure reveals that this molecule is a derivative of hydroxamic acid. For HDAC inhibitors class I and HDACi class II Vorinostat IC50 is found to be near 50 nM. Vorinostat is soluble is ethanol up to 2 mg/ml and in DMSO 65 mg/ml but Vorinostat solubility is found to be very poor in water. Vorinostat stability is about 2 years if stored at -20ºC. Researchers can purchase Vorinostat from different suppliers by paying Vorinostat price which are up to $26 per 100 mg vial and these prices may vary depending upon purity of salt and also vary from supplier to supplier. One of the very first HDAC inhibitors which gain approval from FDA to treat cutaneous T-cell lymphoma was this Vorinostat HDAC inhibitor [3].


PRECLINICAL INVESTIGATIONS ON VORINOSTAT OR SAHA:
Like various other HDAC inhibitors, Vorinostat mechanism is found also to inhibit HDAC class I and HDAC class II enzymes. This inhibitor was found to prolong H2AX foci facilitating cancerous cells to get into an apoptotic phase [4]. It sensitizes the cells of fibrosarcoma to chemotherapy [5]. It has also been found to inhibit the pancreatic tumor cells growth with in the culture [6]. The most advanced and recent application of Vorinostat inhibitor is its induction in cell models of HIV in which it was observed to cause induction of latent expression of HIV [7] to decompose latent HIV reservoir quick in patients treated with HAART  [8].


CLINICAL ACHIEVEMENTS OF SAHA OR VORINOSTAT:
Due to its very remarkable anti-tumor results from in vivo and in vitro models Vorinostat has gained huge importance in many clinical trials. It gives promising results in clinical trials of phase I of advanced tumor patients where Vorinostat was applied as a single chemical agent [9] or used in a combination form with some other drugs [10]. This inhibitor has shown great efficiency in clinical trials phase II in case of ovarian carcinoma [11]. For its great success in clinical trials of phase I, Vorinostat was used as therapeutic agent in clinical trials of phase II in case of metastatic breast carcinoma [12], Glioblastoma multiform [14] and neck and head cancer [13].
The most valuable success of Vorinostat clinical trial is in case of different lymphoma and leukemia cancers. This inhibitor is used as a half part of a combinational therapy in studies of phase I on patients of Non-Hodgkin’s Lymphoma or NHL [15], promising results of this study encouraged the scientists for phase II clinical trials of  Non-Hodgkin’s Lymphoma [16] along with phase II analysis involving both mantle cell lymphoma and NHL patients [17]. Very effective results were found of Vorinostat Zolinza chemotherapy in phase II trials on patients of B cell lymphoma [18] and its involvement as chemotherapeutic agent in patients of cutaneous T cell lymphoma was also observed in clinical trials phase II b [20] in case of refractory CTCL [21]. In case of multiple myeloma patients Vorinostat has passed successfully the clinical trials of phase I [22]. Very encouraging results were obtained by using Vorinostat in phase I studies on patients of myelodysplastic syndrome and leukemia which further prompted its use for advanced research [23].

 

REFERENCES:
1. Marks, P.A.a.B., R., Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotech, 2007.
2. Marks, P.A., Discovery and development of SAHA as an anticancer agent. Oncogene, 2007.
3. Duvic, M.V., J., Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Expert Opinion on Investigational Drugs, 2007.
4. Munshi, A.e.a., Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of γ-H2AX foci. Mol Cancer Ther, 2006.
5. Sampson, E.R.e.a., The histone deacetylase inhibitor vorinostat selectively sensitizes fibrosarcoma cells to chemotherapy. Journal of Orthopaedic Research, 2011.
6. Kumagai, T.e.a., Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cells. International Journal of Cancer, 2007.
7. Archin, N.M.e.a., Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses, 2009.
8. Contreras, X.e.a., Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem., 2009.
9. Kelly, W.K.e.a., Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced Cancer. Journal of Clinical Oncology, 2005.
10. Ramalingam, S.S.e.a., Phase I and Pharmacokinetic Study of Vorinostat, A Histone Deacetylase Inhibitor, in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies. Clin Cancer Res, 2007.
11. Modesitt, S.C.e.a., A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group study. Gynecologic Oncology, 2008.
12. Luu, T.H.e.a., A Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid) in Metastatic Breast Cancer: A California Cancer Consortium Study. Clin Cancer Res, 2008.
13. Blumenschein, G.R.e.a., Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza™, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Investigational New Drugs, 2008.
14. Galanis, E.e.a., Phase II Trial of Vorinostat in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study. Journal of Clinical Oncology, 2008.
15. Stathis, A.e.a., Phase I Study of Decitabine in Combination with Vorinostat in Patients with Advanced Solid Tumors and Non-Hodgkin's Lymphomas. Clin Cancer Res, 2011.
16. Kirschbaum, M.H.e.a., A phase 2 study of vorinostat for treatment of relapsed or refractory Hodgkin lymphoma: Southwest Oncology Group Study S0517. Leukemia & Lymphoma, 2011.
17. Kirschbaum, M.e.a., Phase II Study of Vorinostat for Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma. Journal of Clinical Oncology, 2011.
18. Crump, M.e.a., Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Annals of Oncology, 2008.
19. Mann, B.S.e.a., Vorinostat for Treatment of Cutaneous Manifestations of Advanced Primary Cutaneous T-Cell Lymphoma. Clin Cancer Res, 2007.
20. Olsen, E.A.e.a., Phase IIB Multicenter Trial of Vorinostat in Patients With Persistent, Progressive, or Treatment Refractory Cutaneous T-Cell Lymphoma. Journal of Clinical Oncology, 2007.
21. Duvic, M.e.a., Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood, 2007.
22. Richardson, P.e.a., Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leukemia & Lymphoma, 2008.
23. Manero, G.G.e.a., Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood, 2008.

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S1047 Vorinostat (SAHA, MK0683) Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay. (259) (20)

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