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.
Teraishi
Fuminori
F
Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Wu
Shuhong
S
Sasaki
Jiichiro
J
Zhang
Lidong
L
Zhu
Hong-Bo
HB
Davis
John J
JJ
Fang
Bingliang
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000502:physiology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D005434:Flow Cytometry; D019450:Genes, MDR; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D017239:Paclitaxel / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
C503119:5-((4-methylphenyl)methylene)-2-(phenylamino)-4(5H)-thiazolone; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000814:Aniline Compounds; D000972:Antineoplastic Agents, Phytogenic; D016755:Proto-Oncogene Proteins c-jun; D013844:Thiazoles; D045304:Cytochromes c; D020169:Caspases; D017239:Paclitaxel