Prevention of cisplatin-induced ototoxicity by the inhibition of gap junctional intercellular communication in auditory cells.

Abstract

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 18alpha-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.