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

Abstract

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.

• Authors: Fuminori Teraishi, Shuhong Wu, Jiichiro Sasaki, Lidong Zhang, Hong-Bo Zhu, John J Davis, Bingliang Fang
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 314 Issue 1 Pg. 355-62 (Jul 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15831436 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 5-((4-methylphenyl)methylene)-2-(phenylamino)-4(5H)-thiazolone
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Aniline Compounds
• Antineoplastic Agents, Phytogenic
• Proto-Oncogene Proteins c-jun
• Thiazoles
• Cytochromes c
• Caspases
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis, physiology)
• Aniline Compounds (pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Bone Marrow Cells (drug effects)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytochromes c (metabolism)
• Drug Evaluation, Preclinical
• Drug Resistance, Neoplasm
• Enzyme Activation (drug effects)
• Fibroblasts (drug effects)
• Flow Cytometry
• Genes, MDR
• Genes, p53
• Humans
• Mice
• Mice, Nude
• Neoplasms, Experimental (drug therapy)
• Paclitaxel (pharmacology)
• Proto-Oncogene Proteins c-jun (antagonists & inhibitors, metabolism)
• Thiazoles (pharmacology)