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


METHODS
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.


RESULTS
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 IC(50) value of those drugs correspondingly decreased.


CONCLUSIONS
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.


CONCLUSIONS
Rhamnetin acts as a promising sensitizer to chemotherapy and may be a novel approach to overcome the MDR process of HCC.
Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110016, PR China.
Hui
H
Jia
Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing 100039, PR China.
Qian
Q
Yang
Institute of Toxicology and Pharmacology, Chinese Academy of Military Medical Sciences, Beijing 100850, PR China.
Tao
T
Wang
Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
Yu
Y
Cao
Research and Technology Service Center, The 302nd Hospital, Beijing 100039, PR China.
Qi-Yu
QY
Jiang
Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110016, PR China.
Hong-da
HD
Ma
Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing 100039, PR China.
Hui-Wei
HW
Sun
Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110016, PR China. Electronic address: houmingxiao188@126.com.
Ming-Xiao
MX
Hou
Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing 100039, PR China. Electronic address: yongpingyang@hotmail.com.
Yong-Ping
YP
Yang
Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110016, PR China. Electronic address: fengfanbio@126.com.
Fan
F
Feng
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D051881:Receptor, Notch1; D009536:Niacinamide; D005047:Etoposide; C063423:rhamnetin; D011794:Quercetin; D000077157:Sorafenib; D017239:Paclitaxel
HCC; MDR; MDR-related proteins; MiR-34a; Notch-1 pathway; Rhamnetin