Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cellsReport as inadecuate




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BMC Cancer

, 16:857

Experimental therapeutics and drug development

Abstract

BackgroundVorinostat, a histone deacetylase HDAC inhibitor, is a promising agent for cancer therapy. Combining vorinostat with cisplatin may relax the chromatin structure and facilitate the accessibility of cisplatin, thus enhancing its cytotoxicity. Studies have not yet investigated the effects of the combination of vorinostat and cisplatin on small cell lung cancer SCLC.

MethodsWe first assessed the efficacy of vorinostat with etoposide-cisplatin EP; triple combination and then investigated the effects of cotreatment with vorinostat and cisplatin on H209 and H146 SCLC cell lines. The anticancer effects of various combinations were determined in terms of cell viability, apoptosis, cell cycle distribution, and vorinostat-regulated proteins. We also evaluated the efficacy of vorinostat-cisplatin combination in H209 xenograft nude mice.

ResultsOur data revealed that the triple combination engendered a significant reduction of cell viability and high apoptotic cell death. In addition, vorinostat combined with cisplatin enhanced cell growth inhibition, induced apoptosis, and promoted cell cycle arrest. We observed that the acetylation levels of histone H3 and α-tubulin were higher in combination treatments than in vorinostat treatment alone. Moreover, vorinostat reduced the expression of thymidylate synthase TS, and TS remained inhibited after cotreament with cisplatin. Furthermore, an in vivo study revealed that the combination of vorinostat and cisplatin significantly inhibited tumor growth in xenograft nude mice tumor growth inhibition T-C% = 20.5 %.

ConclusionsCombined treatments with vorinostat promote the cytotoxicity of cisplatin and induce the expression of vorinostat-regulated acetyl proteins, eventually enhancing antitumor effects in SCLC cell lines. Triple combinations with a low dosage of cisplatin demonstrate similar therapeutic effects. Such triple combinations, if applied clinically, may reduce the undesired adverse effects of cisplatin. The effects of the combination of vorinostat and cisplatin should be evaluated further before conducting clinical trials for SCLC treatment.

KeywordsVorinostat Cisplatin SCLC HDAC inhibitor Combination therapy AbbreviationsDMSODimethyl sulfoxide

DTTDithiothreitol

EDTAEthylenediaminetetraacetic acid

EGTAEthylene glycol tetraacetic acid

EPEtoposide-cisplatin

FBSFetal bovine serum

FDAFood and Drug Administration

HATsHistone acetyltransferases

HDACIHDAC inhibitor

HDACsHistone deacetylases

IMDMIscove’s Modified Dulbecco’s Medium

NSCLCNon-small cell lung cancer

PARPPoly ADP-ribose polymerase

PBSPhosphate-buffered saline

PEGPolyethylene glycol

PIPropidium iodide

PMSFPhenylmethylsulfonyl fluoride

RPMIRoswell Park Memorial Institute

SCLCSmall cell lung cancer

TBSTTris-buffered saline Tween-20

TSThymidylate synthase

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Author: Chun-Hao Pan - Ying-Fang Chang - Ming-Shuo Lee - B-Chen Wen - Jen-Chung Ko - Sheng-Kai Liang - Mei-Chih Liang

Source: https://link.springer.com/







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