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VORINOSTAT – AN ANTI HISTONE MODIFYING AGENT

CHROMATIN REMODELLING INHIBITION IN CANCER THERAPY
Histone modification is a very important phenomenon regarding regulation of expression of genes. Acetylation and deacetylation of histones in attached to the genetic material i.e., DNA is done with the help of specific proteins, therefore, in order to inhibit or stimulate the expression of specific genes histone tail modifying proteins can be modified. Histone deacetylating Complexes (HDACs) are one of these modifying proteins which inhibit the expression of some genes by de-acetylating them. Inhibiting these proteins may function in the modulation of gene expression by hyperacetylating them. HDAC inhibitors hence modulate the aberrant expression of genes in cancerous cells. They may inhibit cell division, arrest cell cycle or stimulate apoptosis. A lot of research is being done on different types of HDAC inhibitors in order to use them as anti-cancer therapeutics. Vorinostat is one of such HDAC inhibitors. It is also known as Suberoylanilide Hydroxamic Acid (SAHA) [1]. It is a derivative of hydroxamic acid having anti-cancer capabilities [2]. Vorinostat IC50 is approximately 50 nM for HDAC inhibition against class I and II HDACs. Vorinostat solubility in DMSO is up to 65 mg/ml while in water and ethanol it is soluble only up to 2 mg/ml. if preserved at -20ºC it may remain stable for up to 2 years. Researchers or doctors can buy vorinostat 100 mg vial in $26 for their purposes. Vorinostat price may vary depending upon the purity of the salt. Vorinostat HDAC inhibitor was the first HDAC inhibitor that gained approval from FDA use against cutaneous T-cell lymphoma [3].


MECHANISM OF ACTION AND PRECLINICAL TESTS
Vorinostat SAHA
acts the way other HDAC inhibitors act. It inhibits class I and II HDACs and prolongs the gammaH2AX foci and hence facilitates the cell for apoptosis [4]. It also make fibrosarcoma cells sensitive for chemotherapy [5]. In culture it inhibits the growth of cancerous cells of pancreas [6]. Recently vorinostat SAHA has been employed in the models of HIV cells where it induced the expression of latent HIV [7]. This induction hastens the decomposition of latent HIV reservoirs in the patients treated with HAART [8].
 

CLINICAL TRIALS AND ACHIEVEMENTS
As Vorinostat showed remarkable results in in vivo as well as in vitro models, it has been encouraging to proceed it for clinical trials. Either used as a single agent or as a combinatorial therapy, it gave quite encouraging results in clinical trials of phase I in cancer patients [9-10]. The drug has been tested against different types of cancers e.g., ovarian [11], head and neck [12], Glioblastoma multiforme (GBM) [13] and metastasizing breast cancer [14] where it showed efficacious results clinical trials in phase I and has been proceeded forward. In ovarian cancer it has covered successfully the Phase II trial [11].
Vorinostat clinical trials continued with leukemias and lymphomas and combination therapy was done on patients with Non-Hodgkin’s Lymphoma (NHL) [15] efficacy in phase I prompted its trial on patients with NHL [16] and then MCL (mantle cell lymphoma) in clinical trial phase II [17]. Similarly vorinostat has shown promising results in the studies on patients with B cell lymphoma [18] and CTCL (cutaneous T cell lymphoma) [19] especially refractory cases of CTCL [20] in clinical trials phase II and phase IIb respectively [21]. The studies involving the use of Vorinostat for the patients of multiple myeloma [22], myelodysplastic syndrome and leukemia in clinical trial phase I are very encouraging for the scientists to do more research on this efficacious drug [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. 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.
13. 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.
14.  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.
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. Duvic, M.e.a., Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood, 2007.
21. 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.
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) Vorinostat (suberoylanilide hydroxamic acid, SAHA, MK0683) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay. Vorinostat abrogates productive HPV-18 DNA amplification. (454) (20)

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