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   P-glycoprotein-evading anti-tumor activity of a novel tubulin and HSP90 dual inhibitor in a non-small-cell lung cancer model  
   
نویسنده zhang q. ,zhai s. ,li l. ,li x. ,jiang c. ,zhang c. ,yan b.
منبع journal of pharmacological sciences - 2014 - دوره : 126 - شماره : 1 - صفحه:66 -76
چکیده    P-glycoprotein (p-gp)-induced drug resistance is a major road block for successful cancer chemotherapy. through phenotypic screening,the compound 2-(2-chlorophenylimino)-5-(4-dimethylaminobenzylidene)thiazolidin-4-one (cdbt) was discovered to have potent anti-tumor activity in p-gp over-expressing drug-resistant non-small-cell lung cancer (nsclc) h460taxr cells. here,we report mechanistic investigations of the p-gp-evading anti-tumor activity of cdbt. cdbt is evidently not a p-gp substrate and escapes the p-gp efflux pump. as a novel microtubule and heat shock protein 90 (hsp90) dual targeting inhibitor,cdbt causes the destabilization of microtubules and degradation of hsp90 client proteins craf-1 and erbb2,resulting in cell cycle arrest at the g2/m phase and apoptosis. furthermore,cdbt effectively inhibits tumor growth by 60.4% relative to the vehicle control after intraperitoneal administration at 30 mg/kg for 11 days and shows no toxicity in normal tissues in the nsclc h460taxr xenograft mouse model. our data suggest a novel drug discovery strategy to combat p-gp over-expressing drug-resistant nsclc cancer cells with a single therapeutic agent. © the japanese pharmacological society.
کلیدواژه HSP90; Microtubule; Multidrug resistance; Non-small-cell lung cancer; P-glycoprotein
آدرس school of chemistry and chemical engineering,shandong university,jinan,250100, China, school of chemistry and chemical engineering,shandong university,jinan,250100, China, school of chemistry and chemical engineering,shandong university,jinan,250100, China, school of chemistry and chemical engineering,shandong university,jinan,250100, China, school of chemistry and chemical engineering,shandong university,jinan,250100, China, school of chemistry and chemical engineering,shandong university,jinan,250100, China, school of chemistry and chemical engineering,shandong university,jinan,250100, China
 
     
   
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