Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2015; 21(35): 10126-10136
Published online Sep 21, 2015. doi: 10.3748/wjg.v21.i35.10126
Mechanism of QHF-cisplatin against hepatocellular carcinoma in a mouse model
Tao Chen, Shen-Jun Yuan, Jing Wang, Wei Hu
Tao Chen, Wei Hu, the Third Level of TCM Pharmacology Research Laboratory affiliated to China TCM Administration, Medical Science College of China Three Gorges University, Yichang 443002, Hubei Province, China
Shen-Jun Yuan, Wei Hu, Medical Science College of China Three Gorges University, Yichang 443002, Hubei Province, China
Jing Wang, Department of Medicine, Xinyi People’s Hospital, Xinyi 221400, Jiangsu Province, China
Author contributions: Chen T, Yuan SJ and Wang J contributed equally to this work; Chen T, Yuan SJ, Wang J and Hu W designed the research; Chen T and Wang J performed the research; Yuan SJ analyzed the data; Chen T and Yuan SJ wrote the paper; all authors have read and approved the final version to be published.
Supported by Grants from the Natural Science Foundation of Hubei Province, China, No. 2011CAD039.
Institutional review board statement: The study was reviewed and approved by the Medical Science College of China Three Gorges University Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Experimental Animal Management Committee of China Three Gorges University.
Conflict-of-interest statement: Tao Chen owns the patent for Chinese medicine effective component optimization formula against hepatocellular carcinoma (State Intellectual Property Office of China; patent no. ZL 2006 1 0135871.X.)
Data sharing statement: Technical appendix, statistical code, and dataset are available from the corresponding author at chentaobm@126.com. Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Tao Chen, the Third Level of TCM Pharmacology Research Laboratory affiliated to China TCM Administration, Medical Science College of China Three Gorges University, No. 8 Daxue Road, Yichang 443002, HubeI Province, China. chentao@ctgu.edu.cn
Telephone: +86-717-6397997 Fax: +86 -717-6397959
Received: January 15, 2015
Peer-review started: January 16, 2015
First decision: March 10, 2015
Revised: March 25, 2015
Accepted: April 28, 2015
Article in press: April 28, 2015
Published online: September 21, 2015
Processing time: 245 Days and 22.6 Hours
Abstract

AIM: To study the effects of QHF-cisplatin on H22 hepatocellular carcinoma (HCC) and their mechanisms of action.

METHODS: Sixty BALB/c mice were randomly divided into a model group (n = 48) and a normal control group (n = 12). An HCC xenograft tumor was created by injecting H22 cells directly into the liver parenchyma of the mice. The 48 BALB/c mice in the model group were randomly divided into four groups: QHF, DDP (cisplatin), QHF plus DDP, and model control. The inhibitory effects of these drugs on tumor growth were evaluated by calculating the rate of tumor growth inhibition. The mice were examined by observing their general condition, body weight and survival time. Changes in tumor tissue were observed under an optical microscope. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and α-fetoprotein (AFP) levels in serum were measured. Hepatocyte growth factor (HGF), c-mesenchymal-epithelial transition (c-Met) factor, phosphorylated (p)-c-Met, p38, p-p38, extracellular signal-regulated kinase (ERK), p-ERK and vascular endothelial growth factor (VEGF) levels were evaluated in tumor and liver tissues using western blotting.

RESULTS: Compared with the DDP group, a lower incidence of toxic reactions and a higher survival time were observed in the QHF plus DDP group. Tumor weight was significantly lower in the QHF, DDP and QHF plus DDP groups than in the model control group (0.24 ± 0.07, 0.18 ± 0.03 and 0.14 ± 0.01 g vs 0.38 ± 0.05 g, respectively), and the differences were statistically significant (P < 0.01). The rate of tumor growth inhibition in the QHF, DDP and QHF plus DDP groups was 38.7%, 52.6% and 63.5%, respectively. AST, ALT and AFP levels in serum were significantly lower in the QHF, DDP and QHF plus DDP groups compared to the model control group (P < 0.05). Similarly, HGF, p-c-Met, p-p38, p-ERK and VEGF levels in tumor tissue were significantly lower in the QHF, DDP and QHF plus DDP groups (P < 0.05).

CONCLUSION: QHF and DDP have an antiangiogenic effect on H22 HCC in mice. QHF inhibits tumor growth via blocking the HGF/c-Met signaling pathway, inhibiting p38, ERK and VEGF signaling.

Keywords: QHF formula; Cisplatin; Hepatocellular carcinoma; H22 cells; Hepatocyte growth factor; c-Met

Core tip: QHF and cisplatin (DDP) have an antiangiogenic effect on H22 hepatocellular carcinoma (HCC) in mice. QHF in combination with low-dose DDP has a synergistic antiangiogenic effect and can improve survival and reduce the incidence of toxic reactions in mice with H22 HCC. Moreover, QHF can significantly decrease the expression of hepatocyte growth factor and phosphorylated-c-mesenchymal-epithelial transition factor in liver tumor tissue.