Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model.

Abstract

Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult.

• Authors: Deepali Kurundkar, Ritesh K Srivastava, Sandeep C Chaudhary, Mary E Ballestas, Levy Kopelovich, Craig A Elmets, Mohammad Athar
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 266 Issue 2 Pg. 233-44 (Jan 15 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 23147569 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclins
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Proliferating Cell Nuclear Antigen
• Vorinostat
• TOR Serine-Threonine Kinases
• Histone Deacetylases

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Squamous Cell (drug therapy, pathology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclins (genetics)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Female
• Histone Deacetylase Inhibitors (administration & dosage, pharmacology)
• Histone Deacetylases (genetics)
• Humans
• Hydroxamic Acids (administration & dosage, pharmacology)
• Immunocompromised Host
• Mice
• Mice, Nude
• Proliferating Cell Nuclear Antigen (analysis)
• Signal Transduction (drug effects)
• Skin Neoplasms (drug therapy, pathology)
• TOR Serine-Threonine Kinases (metabolism)
• Vorinostat
• Xenograft Model Antitumor Assays