Rhamnetin induces sensitization of hepatocellular carcinoma cells to a small molecular kinase inhibitor or chemotherapeutic agents

• Published in: Biochimica et biophysica acta Vol. 1860; no. 7; pp. 1417 - 1430
• Main Authors: Jia, Hui, Yang, Qian, Wang, Tao, Cao, Yu, Jiang, Qi-yu, Ma, Hong-da, Sun, Hui-wei, Hou, Ming-xiao, Yang, Yong-ping, Feng, Fan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2016
• Subjects: agar; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; breast neoplasms; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Survival - drug effects; cell viability; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; drug therapy; etoposide; Etoposide - pharmacology; flow cytometry; Gene Expression Regulation, Neoplastic; HCC; Hep G2 Cells; hepatoma; Humans; Inhibitory Concentration 50; Liver Neoplasms - drug therapy; Liver Neoplasms - enzymology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; MDR; MDR-related proteins; mice; Mice, SCID; MicroRNAs - genetics; MicroRNAs - metabolism; MiR-34a; multiple drug resistance; neoplasm cells; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Notch-1 pathway; P-glycoproteins; paclitaxel; Paclitaxel - pharmacology; Phenylurea Compounds - pharmacology; pro-apoptotic proteins; Protein Kinase Inhibitors - pharmacology; quantitative polymerase chain reaction; Quercetin - analogs & derivatives; Quercetin - pharmacology; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - metabolism; Rhamnetin; signal transduction; Signal Transduction - drug effects; stress response; Transfection; Western blotting; Xenograft Model Antitumor Assays; Rhamnetin; MDR-related proteins; HCC; MDR; MiR-34a; Notch-1 pathway
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.04.007

The rapid development of multi-drug resistance (MDR) process has hindered the effectiveness of advanced hepatocellular carcinoma (HCC) treatments. Notch-1 pathway, which mediates the stress-response, promotes cell survival, EMT (epithelial–mesenchymal transition) process and induces anti-apoptosis in cancer cells, would be a potential target for overcoming MDR process. This study investigated the potential application of rhamnetin, a specific inhibitor of Notch-1 pathway, in anti-tumor drug sensitization of HCC treatment. The expression of miR-34a, proteins belonging to Notch-1 signaling pathway or MDR-related proteins was detected by quantitative polymerase chain reaction (qPCR) and western blot assay. To identify whether rhamnetin induces the chemotherapeutic sensitization in HCC cells, the MTT-assays, flow cytometry, soft agar, trans-well and nude mice assays were performed. The endogenous expression of miR-34a was significantly increased and the expression of Notch-1 and Survivin was downregulated after rhamnetin treatment. Treatment of rhamnetin also reduced the expression of MDR related proteins P-GP (P-glycoprotein) and BCRP (breast cancer resistance protein). Rhamnetin increased the susceptibility of HCC cells and especially HepG2/ADR, a MDR HCC cell line, to a small molecular kinase inhibitor sorafenib or chemotherapeutic drugs etoposide and paclitaxel. The IC50 value of those drugs correspondingly decreased. Together, our findings suggest that rhamnetin treatment may attenuate the MDR process in HCC cells. These findings may contribute to more effective strategies for HCC therapy. Rhamnetin acts as a promising sensitizer to chemotherapy and may be a novel approach to overcome the MDR process of HCC. •Notch-1 pathway would be a potential target for overcoming MDR which hinders the effectiveness of advanced HCC treatments.•Rhamnetin increased the susceptibility of HCC cells to a small molecular kinase inhibitor sorafenib or chemotherapeutic drugs.•Rhamnetin treatment reduced proteins belonging to Notch-1 signaling pathway and MDR-related pathway.•Rhamnetin acts as a promising sensitizer to chemotherapy and may be a novel approach to overcome the MDR process of HCC.