The clinical use of the
antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect.
Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the
cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl(-) channel not only involved in
chloride secretion but as well in
glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against
cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR,
CFTR(inh)-172, prevents
cisplatin-induced cell death and apoptosis by modulating the intracellular
reactive oxygen species balance and the intracellular GSH concentration. This CFTR(inh)-172-mediated protective effect occurs without affecting cellular
cisplatin uptake or the formation of
platinum-
DNA adducts. The protective effect of
CFTR(inh)-172 in
cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single
cisplatin injection (5 mg/kg), rats exhibited
renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with
CFTR(inh)-172 (1 mg/kg) prior to
cisplatin injection significantly prevented these deleterious
cisplatin-induced nephrotoxic effects. Finally, we demonstrate that
CFTR(inh)-172 does not impair
cisplatin-induced cell death in the
cisplatin-sensitive A549
cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during
cisplatin treatment without affecting its antitumor efficacy.