Azole antifungal drugs have been shown to enhance the cytotoxicity of
antimitotic drugs in
P-glycoprotein (P-gp)-overexpressing-resistant
cancer cells. Herein, we examined two
azole antifungal drugs,
terconazole (TCZ) and
butoconazole (BTZ), previously unexplored in resistant
cancers. We found that both TCZ and BTZ increased cytotoxicity in
vincristine (VIC)-treated P-gp-overexpressing
drug-resistant KBV20C
cancer cells. Following detailed analysis, low-dose VIC + TCZ exerted higher cytotoxicity than co-treatment with VIC + BTZ. Furthermore, we found that VIC + TCZ could increase apoptosis and induce G2 arrest. Additionally, low-dose TCZ could be combined with various
antimitotic drugs to increase their cytotoxicity in P-gp-overexpressing
antimitotic drug-resistant
cancer cells. Moreover, TCZ exhibited P-gp inhibitory activity, suggesting that the inhibitory activity of P-gp plays a role in sensitization afforded by VIC + TCZ co-treatment. We also evaluated the cytotoxicity of 12
azole antifungal drugs at low doses in
drug-resistant
cancer cells. VIC + TCZ, VIC +
itraconazole, and VIC +
posaconazole exhibited the strongest cytotoxicity in P-gp-overexpressing KBV20C and MCF-7/ADR-resistant
cancer cells. These drugs exerted robust P-gp inhibitory activity, accompanied by
calcein-AM substrate efflux. Given that
azole antifungal drugs have long been used in clinics, our results, which reposition
azole antifungal drugs for treating P-gp-overexpressing-resistant
cancer, could be employed to treat patients with
drug-resistant
cancer rapidly.