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.
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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.)
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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
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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)
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