Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells.
Vorinostat, 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).



We 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.



Our 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 %).



Combined 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.
Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Po-Ai Street, Hsinchu, 300, Taiwan.
Chun-Hao
CH
Pan
Department of Biological Science and Technology, National Chiao Tung University, 75 Po-Ai Street, Hsinchu, 300, Taiwan.
Ying-Fang
YF
Chang
Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Po-Ai Street, Hsinchu, 300, Taiwan.
Ming-Shuo
MS
Lee
Department of Biological Science and Technology, National Chiao Tung University, 75 Po-Ai Street, Hsinchu, 300, Taiwan.
B-Chen
BC
Wen
Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, No. 25, Lane 442, Section 1, Jingguo Road, Hsinchu, 300, Taiwan.
Jen-Chung
JC
Ko
Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, No. 25, Lane 442, Section 1, Jingguo Road, Hsinchu, 300, Taiwan. paukai1111@yahoo.com.tw.
Sheng-Kai
SK
Liang
Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Po-Ai Street, Hsinchu, 300, Taiwan. mcliang@nctu.edu.tw.|Department of Biological Science and Technology, National Chiao Tung University, 75 Po-Ai Street, Hsinchu, 300, Taiwan. mcliang@nctu.edu.tw.
Mei-Chih
0000-0002-7389-2455
MC
Liang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000473:pathology; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D002945:Cisplatin
Cisplatin; Combination therapy; HDAC inhibitor; SCLC; Vorinostat