P-glycoprotein-evading anti-tumor activity of a novel tubulin and HSP90 dual inhibitor in a non-small-cell lung cancer model

P-glycoprotein (p-gp)-induced drug resistance is a major road block for successful cancer chemotherapy. through phenotypic screening,the compound 2-(2-chlorophenylimino)-5-(4-dimethylaminobenzylidene)thiazolidin-4-one (cdbt) was discovered to have potent anti-tumor activity in p-gp over-expressing drug-resistant non-small-cell lung cancer (nsclc) h460taxr cells. here,we report mechanistic investigations of the p-gp-evading anti-tumor activity of cdbt. cdbt is evidently not a p-gp substrate and escapes the p-gp efflux pump. as a novel microtubule and heat shock protein 90 (hsp90) dual targeting inhibitor,cdbt causes the destabilization of microtubules and degradation of hsp90 client proteins craf-1 and erbb2,resulting in cell cycle arrest at the g2/m phase and apoptosis. furthermore,cdbt effectively inhibits tumor growth by 60.4% relative to the vehicle control after intraperitoneal administration at 30 mg/kg for 11 days and shows no toxicity in normal tissues in the nsclc h460taxr xenograft mouse model. our data suggest a novel drug discovery strategy to combat p-gp over-expressing drug-resistant nsclc cancer cells with a single therapeutic agent. © the japanese pharmacological society.