title: CLC604 preferentially inhibits the growth of HER2-overexpressing cancer cells and sensitizes these cells to the inhibitory effect of Taxol in vitro and in vivo.
abstract: HER2 has become a solicitous therapeutic target in metastatic and clinical drug-resistant cancer. Here, we evaluated whether or not 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) and its furopyrazole and thienopyrazole analogues repress the expression of the HER2 protein. Among the test compounds, (1-benzyl-3-(p-hydroxymethylphenyl)-5-methylfuro[3,2-c]pyrazol) (CLC604), an isosteric analogue of YC-1, significantly suppressed the expression of HER2, and preferentially inhibited cell proliferation and induced apoptosis in HER2-overexpressing cancer cells. Our results revealed that CLC604 reduced HER2 expression through a post-transcriptional mechanism and involvement of proteasomal activity. CLC604 disrupted the association of 90-kDa heat shock protein (Hsp90) with HER2 resulting from the inhibition of Hsp90 ATPase activity. Moreover, we found that CLC604 significantly enhanced the antitumor efficacy of clinical drugs against HER2-overexpressing tumors and efficiently reduced HER2-induced drug resistance in vitro and in vivo. These findings suggest that CLC604 should be developed further as a novel antitumor drug candidate for the treatment of drug-resistant cancer.
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: Jang-Chang
authors.initials: JC
authors.lastname: Lee
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Chou
authors.forename: Jin-Chemg
authors.initials: JC
authors.lastname: Lien
authors.forename: Jia-Chiun
authors.initials: JC
authors.lastname: Wu
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.forename: Chao-Ho
authors.initials: CH
authors.lastname: Chung
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Lee
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Tzong-Der
authors.initials: TD
authors.lastname: Way
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D061067:Antibodies, Monoclonal, Humanized; D004317:Doxorubicin; D005047:Etoposide; D005663:Furans; D018841:HSP90 Heat-Shock Proteins; D007191:Indazoles; D017239:Paclitaxel; D011720:Pyrazoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C588065:1-benzyl-3-(p-hydroxymethylphenyl)-5-methylfuro(3,2-c)pyrazole; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C508053:ERBB2 protein, human