title: Cisplatin and oxaliplatin inhibit gap junctional communication by direct action and by reduction of connexin expression, thereby counteracting cytotoxic efficacy.
abstract: Cisplatin [cis-diamminedichloroplatinum(II)]/oxaliplatin [1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II)] toxicity is enhanced by functional gap junctions between treated cells, implying that inhibition of gap junctions may decrease cytotoxic activity of these platinum-based agents. This study investigates the effect of gap junction modulation by cisplatin/oxaliplatin on cytotoxicity in a transformed cell line. The effects were explored using junctional channels expressed in transfected HeLa cells and purified hemichannels. Junctional channels showed a rapid, dose-dependent decrease in dye coupling with exposure to cisplatin/oxaliplatin. With longer exposure, both compounds also decreased connexin expression. Both compounds inhibit the activity of purified connexin hemichannels, over the same concentration range that they inhibit junctional dye permeability, demonstrating that inhibition occurs by direct interaction of the drugs with connexin protein. Cisplatin/oxaliplatin reduced the clonogenic survival of HeLa cells at low density and high density in a dose-dependent manner, but to a greater degree at high density, consistent with a positive effect of gap junctional intercellular communication (GJIC) on cytotoxicity. Reduction of GJIC by genetic or pharmacological means decreased cisplatin/oxaliplatin toxicity. At low cisplatin/oxaliplatin concentrations, where effects on connexin channels are minimal, the toxicity increased with increased cell density. However, higher concentrations strongly inhibited GJIC, and this counteracted the enhancing effect of greater cell density on toxicity. The present results indicate that inhibition of GJIC by cisplatin/oxaliplatin decreases their cytotoxicity. Direct inhibition of GJIC and reduction of connexin expression by cisplatin/oxaliplatin may thereby compromise the effectiveness of these compounds and be a factor in the development of resistance to this class of chemotherapeutic agents.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Tianhui
authors.initials: T
authors.lastname: You
authors.forename: Dongdong
authors.initials: D
authors.lastname: Yuan
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Hong
authors.forename: Bo
authors.initials: B
authors.lastname: He
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Wang
authors.forename: Xuhui
authors.initials: X
authors.lastname: Tong
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001693:Biological Transport, Active; D015153:Blotting, Western; D002450:Cell Communication / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004396:Coloring Agents; D017630:Connexins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D017629:Gap Junctions / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin
chemical_list: D000970:Antineoplastic Agents; D004396:Coloring Agents; D017630:Connexins; D008081:Liposomes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin