Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
Mol Med Rep. 2013 Aug;8(2):638-44. doi: 10.3892/mmr.2013.1546. Epub 2013 Jun 25.
Gap junctions (GJs) enhance the cytotoxicity of specific cancer chemotherapeutic drugs and therefore, the inhibition of functional GJs may represent a mechanism by which the toxicity of chemotherapeutics in cancer cells can be reduced. In the present study, the effects and mechanisms of paclitaxel and docetaxel on GJ intercellular communication (GJIC) and the modulation of drug cytotoxicity were investigated in HeLa cells that were stably transfected with the connexin (Cx) 32 expression plasmid. Paclitaxel, but not docetaxel, was observed to inhibit dye‑coupling through junctional channels. Gating closure rather than the alteration of Cx32 expression or its membrane localization was responsible for the inhibitory action of paclitaxel on GJ function following short‑term exposure. The results revealed that the cytotoxicity of paclitaxel or docetaxel increased in the presence of functional GJs compared with that observed when GJIC was suppressed. In addition, paclitaxel‑induced downregulation of GJIC decreased the cytotoxicity of paclitaxel in the presence of functional GJs compared with that of docetaxel, which did not affect Cx32 channels. These observations demonstrated that the differential effects of paclitaxel and docetaxel on GJIC may affect the cytotoxicity of chemotherapeutic drugs. The present study provides a promising new approach to select antineoplastics and improve drug efficacy in carcinoma cells that form GJs.
间隙连接 (GJ) 增强了特定癌症化疗药物的细胞毒性，因此，功能性 GJ 的抑制可能代表了降低癌细胞中化疗药物毒性的一种机制。在本研究中，通过稳定转染间隙连接蛋白 32 (Cx32) 表达质粒的 HeLa 细胞，研究了紫杉醇和多西紫杉醇对 GJ 细胞间通讯 (GJIC) 的影响及其对药物细胞毒性的调节作用。结果表明，与 GJIC 被抑制时相比，紫杉醇而非多西紫杉醇观察到通过连接通道抑制染料偶联。与 Cx32 表达或其膜定位的改变相反，短时间暴露后，紫杉醇对 GJ 功能的抑制作用是由连接门控关闭引起的。结果表明，与 GJIC 被抑制时相比，在存在功能性 GJ 的情况下，紫杉醇或多西紫杉醇的细胞毒性增加。此外，与不影响 Cx32 通道的多西紫杉醇相比，紫杉醇诱导的 GJIC 下调降低了功能性 GJ 存在时紫杉醇的细胞毒性。这些观察结果表明，紫杉醇和多西紫杉醇对 GJIC 的不同作用可能影响化疗药物的细胞毒性。本研究为选择抗肿瘤药物和提高形成 GJ 的癌细胞中药物疗效提供了一种有前途的新方法。
