title: Propofol depresses cisplatin cytotoxicity via the inhibition of gap junctions.
abstract: The general anesthetic, propofol, affects chemotherapeutic activity, however, the mechanism underlying its effects remains to be fully elucidated. Our previous study showed that tramadol and flurbiprofen depressed the cytotoxicity of cisplatin via the inhibition of gap junction (GJ) intercellular communication (GJIC) in connexin (Cx)32 HeLa cells. The present study investigated whether the effects of propofol on the cytotoxicity of cisplatin were mediated by GJ in U87 glioma cells and Cx26‑transfected HeLa cells. Standard colony formation assay was used to determine the cytotoxicity of cisplatin. Parachute dye coupling assay was used to measure GJ function, and western blot analysis was used to determine the expression levels of Cx32. The results revealed that exposure of the U87 glioma cells and the Cx26-transfected HeLa cells to cisplatin for 1 h reduced clonogenic survival in low density cultures (without GJs) and high density cultures (with GJs). However, the toxic effect was higher in the high density culture. In addition, pretreatment of the cells with propofol significantly reduced cisplatin‑induced cytotoxicity, but only in the presence of functional GJs. Furthermore, propofol significantly inhibited dye coupling through junctional channels, and a long duration of exposure of the cells to propofol downregulated the expression levels of Cx43 and Cx26. These results demonstrated that the inhibition of GJIC by propofol affected the therapeutic efficacy of chemotherapeutic drugs. The present study provides evidence of a novel mechanism underlying the effects of analgesics in counteracting chemotherapeutic efficiency.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Tumor Research Institute, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang 830000, P.R. China.
authors.forename: Xiyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Tumor Research Institute, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang 830000, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ge
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D000072259:Connexin 26; D018031:Connexin 43 / Q000235:genetics; D017630:Connexins / Q000235:genetics; D004347:Drug Interactions; D017629:Gap Junctions / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015742:Propofol / Q000494:pharmacology*
chemical_list: D018686:Anesthetics, Intravenous; D000970:Antineoplastic Agents; D018031:Connexin 43; D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26; D002945:Cisplatin; D015742:Propofol