title: P-glycoprotein-evading anti-tumor activity of a novel tubulin and HSP90 dual inhibitor in a non-small-cell lung cancer model.
abstract: 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.
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhang
authors.forename: Shumei
authors.initials: S
authors.lastname: Zhai
authors.forename: Liwen
authors.initials: L
authors.lastname: Li
authors.forename: Xiue
authors.initials: X
authors.lastname: Li
authors.forename: Cuijuan
authors.initials: C
authors.lastname: Jiang
authors.forename: Chengke
authors.initials: C
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D014404:Tubulin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D048008:TNF Receptor-Associated Factor 3; D014404:Tubulin; C508053:ERBB2 protein, human