Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China; Department of Anesthesia, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, People's Republic of China.
Toxicology. 2013 Oct 4;312:149-57. doi: 10.1016/j.tox.2013.08.013. Epub 2013 Aug 23.
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.
一些亲脂性他汀类药物已被报道能增强抗肿瘤药物引起的毒性，但潜在的机制尚不清楚。在本研究中，作者研究了缝隙连接细胞间通讯（GJIC）在辛伐他汀对依托泊苷诱导的细胞毒性中的作用中是否涉及 Cx43。结果表明，治疗水平依托泊苷细胞毒性的主要成分是由连接蛋白 43（Cx43）组成的缝隙连接介导的，辛伐他汀在不引起细胞毒性的剂量下增加缝隙连接偶联，增强依托泊苷的毒性。辛伐他汀对 GJIC 的增强作用与抑制 PKC 介导的 Cx43 丝氨酸 368 磷酸化有关，随后该药物增强了 Cx43 的膜定位。本研究提示，缝隙连接的上调可能被用于提高抗癌化疗的疗效。
