Simvastatin-induced up-regulation of gap junctions composed of connexin 43 sensitize Leydig tumor cells to etoposide: An involvement of PKC pathway

Some of lipophilic statins have been reported to enhance toxicities induced by antineoplastic agents but the underling mechanism is unclear. The authors investigated the involvement of Cx43-mediated gap junction intercellular communication (GJIC) in the effect of simvastatin on the cellular toxicity...

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Bibliographic Details
Published in:Toxicology (Amsterdam) 2013-10, Vol.312, p.149-157
Main Authors: Wang, Lingzhi, Fu, Yanni, Peng, Jianxin, Wu, Dengpan, Yu, Meiling, Xu, Chengfang, Wang, Qin, Tao, Liang
Format: Article
Language:English
Subjects:
Animals
antineoplastic agents
Antineoplastic Agents, Phytogenic - pharmacology
cell communication
Cell Communication - drug effects
Cell Line, Tumor
Cell Survival - drug effects
Connexin 43
Connexin 43 - analysis
Connexin 43 - metabolism
cytotoxicity
Emergency
Etoposide
Etoposide - pharmacology
Gap junction
gap junctions
Gap Junctions - chemistry
Gap Junctions - drug effects
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
Leydig Cell Tumor - drug therapy
Leydig Cell Tumor - pathology
Mice
phosphorylation
PKC
protein kinase C
Protein Kinase C - physiology
Simvastatin
Simvastatin - pharmacology
toxicology
Up-Regulation
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Summary:Some of lipophilic statins have been reported to enhance toxicities induced by antineoplastic agents but the underling mechanism is unclear. The authors investigated the involvement of Cx43-mediated gap junction intercellular communication (GJIC) in the effect of simvastatin on the cellular toxicity induced by etoposide in this study. The results showed that a major component of the cytotoxicity of therapeutic levels of etoposide is mediated by gap junctions composed of connexin 43(Cx43) and simvastatin at the dosage which does not induce cytotoxicity enhances etoposide toxicity by increasing gap junction coupling. The augmentative effect of simvastatin on GJIC was related to the inhibition of PKC-mediated Cx43 phosphorylation at ser368 and subsequent enhancement of Cx43 membrane location induced by the agent. The present study suggests the possibility that upregulation of gap junctions may be utilized to increase the efficacy of anticancer chemotherapies.
ISSN:0300-483X
1879-3185
DOI:10.1016/j.tox.2013.08.013