title: Anti-tumor selectivity of a novel tubulin and HSP90 dual-targeting inhibitor in non-small cell lung cancer models.
abstract: Dose-limiting toxicity is a main road blocker for successful cancer chemotherapy. By phenotype screening, a novel chemical agent 2-(2-Chlorophenylimino)-5-(4-dimethylamino-benzylidene) thiazolidin-4-one (CDBT) was found to strongly inhibit the proliferation of non-small cell lung cancer (NSCLC) cells H460 and H322 while displaying no obvious toxicity to normal fast-dividing fibroblast cells NHFB and WI-38 at a concentration 100-fold higher than its EC50 to NSCLC cells. CDBT targets microtubule and heat shock protein 90 (HSP90) simultaneously with moderate affinities compared to microtubule targeting Colchicine and HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygaldanamcyin (17-DMAG). CDBT blocks microtubule formation, decreases cancer-essential proteins CRAF-1, ERBB2 and phosphorylated AKT, and causes G2/M arrest and apoptosis. The moderate inhibitory effects of CDBT on targets require a higher cellular concentration of targets, a situation only exist in cancer cells. This accounts for its good cancer selectivity. Furthermore, CDBT effectively inhibits tumor growth by 62.4% relative to the vehicle control after i.p. administration at 30 mg/kg for 11 days while showing no toxicity to normal tissues in NSCLC H460 xenograft mouse model.
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, 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: Hongyu
authors.initials: H
authors.lastname: Zhou
authors.forename: Aifeng
authors.initials: A
authors.lastname: Liu
authors.forename: Gaoxing
authors.initials: G
authors.lastname: Su
authors.forename: Qingxin
authors.initials: Q
authors.lastname: Mu
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014404:Tubulin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D014404:Tubulin
keywords: Anti-tumor selectivity; HSP90; Non-small cell lung cancer; Promiscuous; Tubulin