Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2017; 23(23): 4233-4242
Published online Jun 21, 2017. doi: 10.3748/wjg.v23.i23.4233
Inhibition of N-methyl-N-nitrosourea-induced gastric tumorigenesis by Liuwei Dihuang Pill in db/db mice
Shan Zhuang, Yong-Mei Jian, Yong-Ning Sun
Shan Zhuang, Yong-Mei Jian, Yong-Ning Sun, Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
Author contributions: Sun YN contributed to the conception and design of the study; Zhuang S and Jian YM contributed to acquisition, analysis and interpretation of the data; all authors drafted the article and made critical revisions related to the intellectual content of the manuscript, and approved the final version of the article to be published.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Shanghai Sixth People’s Hospital.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (IACUC Protocol No. 2017-0002).
Conflict-of-interest statement: All authors declare that there are no conflicts of interest.
Data sharing statement: All authors declare that no additional data are available.
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: Yong-Ning Sun, PhD, Director, Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai 200233, China. ynsun@sjtu.edu.cn
Telephone: +86-21-20953075 Fax: +86-21-20953075
Received: February 9, 2017
Peer-review started: February 9, 2017
First decision: March 16, 2017
Revised: March 30, 2017
Accepted: May 9, 2017
Article in press: May 9, 2017
Published online: June 21, 2017
Abstract
AIM

To investigate the inhibitory effect of Liuwei Dihuang Pill (LDP) on gastric tumorigenesis induced by N-methyl-N-nitrosourea (MNU) in diabetic mice.

METHODS

Four-week-old mice were divided into four groups: A, 12 db/m mice treated with MNU and saline, as the non-diabetic control; B, 12 db/db mice treated with MNU and saline, as the diabetic control; C, 12 db/db mice treated with MNU and metformin, as the positive control; and D, 12 db/db mice treated with MNU and LDP. MNU was administrated for 20 wk to induce gastric carcinogenesis. LDP was administrated for 10 wk for improvement of insulin resistance. Body weight and food intake were measured every week. Blood samples were collected for assays of fasting blood glucose, insulin, insulin-like growth factor (IGF)-1, adiponectin and leptin. Stomach tissues were collected for histopathological analysis, immunohistochemical staining of Ki67, quantitative reverse transcription-polymerase chain reaction and western blotting.

RESULTS

The incidence of MNU-induced gastric dysplasia was significantly elevated in diabetic (db/db) mice relative to the control (db/m) mice. The incidence of gastric dysplasia was significantly reduced by LDP with suppression of cell proliferation, as demonstrated by a decrease in Ki67 staining. Hyperglycemia, hyperinsulinemia and serum IGF-1 were inhibited by LDP. Expression of IGF-1 and insulin receptor mRNAs was decreased, phosphorylation of IGF-1 receptor and AKT protein was reduced in the stomach tissues by LDP. In addition, adiponectin was increased and leptin was decreased in the serum by LDP.

CONCLUSION

LDP decreased risk of gastric dysplasia in type 2 diabetic mice by down-regulation of IGF and insulin activity and correction of adipokines disorders.

Keywords: Diabetes, Gastric cancer, Liuwei Dihuang Pill, Insulin, Insulin-like growth factor

Core tip: Type 2 diabetes is reported to increase risk of gastric carcinogenesis, partly by hyperinsulinemia, hyperglycemia, excessive activation of insulin-like growth factor (IGF)-1, and disorders of adipokines. In this study, we demonstrated that Liuwei Dihuang Pill decreased the risk of gastric tumorigenesis in type 2 diabetic mice by alleviating insulin resistance and decreasing IGF-1 and insulin activity, followed by down-regulation of the IGF-1/AKT signaling pathway. The improvement in adiponectin and leptin may also contribute to the effects.