P-glycoprotein-independent apoptosis induction by a novel synthetic compound, MMPT [5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone].

To develop new anticancer agents that are effective for treatment of chemoresistant tumors, we screened a chemical library for compounds that can effectively kill both paclitaxel-sensitive lung cancer cell H460 and P-glycoprotein-overexpressing paclitaxel-resistant cell H460/TaxR. A synthetic compound, MMPT (5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone), was identified to induce cytotoxic effects in both H460 and H460/TaxR cells but not in normal fibroblasts. MMPT effectively inhibited the growth of several human lung cancer cell lines in a dose-dependent manner, with 50% inhibitory concentrations ranging from 4.9 to 8.0 microM. The inhibitory effect on cancer cells is independent of the status of p53 and P-glycoprotein. Moreover, MMPT had no obvious toxic effects on normal human fibroblasts and mesenchymal stem cells at the 50% inhibitory concentration for lung cancer cell lines. Treating lung cancer cells with MMPT-induced apoptosis with caspase-3, -8, -9, and poly(ADP-ribose) polymerase cleavage and cytochrome c release from mitochondria. MMPT-induced apoptosis was abrogated when c-Jun N-terminal kinase (JNK) activation was blocked with a specific JNK inhibitor, SP600125. Furthermore, in vivo administration of MMPT suppressed human H460 xenograft tumor growth in nude mice. Our results suggest that MMPT may induce tumor-selective cell killing in both P-glycoprotein-negative and -positive cancer cells and could be a new anticancer agent for treatment of refractory tumors.