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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 14, 2005; DOI: 10.1124/jpet.105.085654

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Received for publication March 3, 2005.
Revised April 8, 2005.
Accepted for publication April 8, 2005.

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

Fuminori Teraishi 1, Shuhong Wu 2, Jiichiro Sasaki 1, Lidong Zhang 1, Hongbo Zhu 1, John J. Davis 1, Bingliang Fang 1*

1 M. D. Anderson Cancer Center 2 M.D. Anderson.org

* Address correspondence to: E-mail: bfang{at}mdanderson.org

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, 5-[(4-methylphenyl) methylene]-2-(phenylamino)-4(5H)-thiazolone (MMPT), 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 mM. 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 PARP 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 P- glycoprotein-positive cancer cells and could be a new anticancer agent for treatment of refractory tumors.


Key words: Cancer, Chemotherapy, MAP kinase, P-glycoprotein, Resistance, apoptosis


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[Abstract] [Full Text] [PDF]


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