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.
Subject(s)
Breast Neoplasms/drug therapy , Furans/pharmacology , Ovarian Neoplasms/drug therapy , Paclitaxel/pharmacology , Pyrazoles/pharmacology , Receptor, ErbB-2/metabolism , Animals , Antibiotics, Antineoplastic/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Doxorubicin/pharmacology , Etoposide/pharmacology , Female , Furans/therapeutic use , HSP90 Heat-Shock Proteins/drug effects , HSP90 Heat-Shock Proteins/metabolism , Humans , Indazoles/pharmacology , Indazoles/therapeutic use , Mice , Mice, SCID , Neoplasm Transplantation , Pyrazoles/therapeutic use , Receptor, ErbB-2/biosynthesis , Trastuzumab , Xenograft Model Antitumor AssaysABSTRACT
In the present study, we successively extracted the pu-erh raw tea with methanol (PR-1), chloroform (PR-2), ethyl acetate (PR-3), n-butanol (PR-4), and water (PR-5). Among these extracts, PR-3 extract contained ingredients with the most effective hypolipidemic potential and was further purified by column chromatography. Moreover, chronic administration of PR-3 provoked a significant reduction in levels of serum triglyceride and low-density lipoprotein (LDL) in rats. Our study demonstrated that fraction 5 from the PR-3 extract (PR-3-5s) showed a hypolipidemic effect in human hepatoma HepG2 cells. PR-3-5s decreased the expression of fatty acid synthase (FASN) and inhibited the activity of acetyl-coenzyme A carboxylase (ACC) by stimulating AMP-activated protein kinase (AMPK) through the LKB1 pathway. Moreover, PR-3-5s blocked the progression of the cell cycle at the G1 phase by inducing p53 expression and in turn upregulating p21 expression.
