Cis-diamminedichloroplatinum (
cisplatin) is an effective chemotherapeutic drug for
cancer therapy. However, most patients treated with
cisplatin are at a high risk of
ototoxicity, which causes severe
hearing loss. Inspired by the "Good Samaritan effect" or "bystander effect" from gap junction coupling, we investigated the role of gap junctions in
cisplatin-induced
ototoxicity as a potential therapeutic method. We showed that
connexin 43 (
Cx43) was highly expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, mediating cell-cell communication. The viability of HEI-OC1 cells was greatly decreased by
cisplatin treatment, and
cisplatin-treated HEI-OC1 cells showed lower
Cx43 expression compared to that of untreated HEI-OC1 cells. In particular, high accumulation of
Cx43 was observed around the nucleus of
cisplatin-treated cells, whereas scattered punctuate expression of
Cx43 was observed in the cytoplasm and membrane in normal cells, suggesting that
cisplatin may interrupt the normal gap junction communication by inhibiting the trafficking of
Cx43 to cell membranes in HEI-OC1 cells. Interestingly, we found that the inhibition of gap junction activity reduced
cisplatin-induced apoptosis of auditory hair cells.
Cx43 siRNA- or 18α-GA-treated HEI-OC1 cells showed higher cell viability compared to control HEI-OC1 cells during
cisplatin treatment; this was also supported by fluorescence recovery after photobleaching studies. Inhibition of gap junction activity reduced recovery of
calcein acetoxymethyl ester fluorescence compared to control cells. Additionally, analysis of the mechanisms involved demonstrated that highly activate
extracellular signal-regulated kinase and
protein kinase B, combined with inhibition of gap junctions may promote cell viability during
cisplatin treatment.