Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 21, 2019; 25(15): 1854-1864
Published online Apr 21, 2019. doi: 10.3748/wjg.v25.i15.1854
Extract of Cycas revoluta Thunb. enhances the inhibitory effect of 5-fluorouracil on gastric cancer cells through the AKT-mTOR pathway
Xing-Liang Cui, Ke-Ji Li, Hai-Xia Ren, Yong-Jian Zhang, Xiao-Dong Liu, Bao-Guo Bu, Lei Wang
Xing-Liang Cui, Hai-Xia Ren, Yong-Jian Zhang, Xiao-Dong Liu, Bao-Guo Bu, Department of Gastroenterology, Affiliated Hospital of Hebei University of Engineering, Handan 056001, Hebei Province, China
Ke-Ji Li, Department of Surgery, Affiliated Hospital of Hebei University of Engineering, Handan 056001, Hebei Province, China
Lei Wang, Department of Pathology, Medical College of Hebei University of Engineering, Handan 056000, Hebei Province, China
Author contributions: Wang L and Cui XL designed the research; Li KJ, Ren HX, Zhang YJ and Cui XL performed the research; Liu XD and Bu BG analyzed the data; Wang L and Cui XL wrote the paper.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of the Affiliated Hospital of Hebei University of Engineering.
Conflict-of-interest statement: We declare no conflict of interest.
Data sharing statement: 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/
Corresponding author: Lei Wang, MA, MSc, Associate Professor, Department of Pathology, Medical College of Hebei University of Engineering, No. 42 Congtai Road, Handan 056000, Hebei Province, China. wangleinv1975@126.com
Telephone: +86-13131048342 Fax: +86-310-8575116
Received: February 21, 2019
Peer-review started: February 21, 2019
First decision: March 5, 2019
Revised: March 10, 2019
Accepted: March 16, 2019
Article in press: March 16, 2019
Published online: April 21, 2019
Processing time: 56 Days and 17 Hours
Abstract
BACKGROUND

Gastric cancer is one of the most common and deadly malignancies worldwide. Despite recent medical progress, the 5-year survival rate of gastric cancer is still unsatisfactory. 5-fluorouracil (5-Fu) is one of the first-line antineoplastic treatments for gastric cancer, as it can effectively induce cancer cell apoptosis. However, the effect of 5-Fu is limited due to drug resistance of the malignant tumor. Previous studies have reported that Sotetsuflavone from Cycas revoluta Thunb. can markedly suppress lung cancer cell proliferation by apoptosis, though its effect on gastric cancer remains unknown.

AIM

To investigate the inhibitory effect of Cycas revoluta Thunb. and to determine whether it can overcome gastric cancer cell drug resistance to 5-Fu.

METHODS

Cell viability was examined to determine whether the natural extract of Cycas revoluta Thunb. induced gastric cancer cell death. The half-maximal effective concentration and the half-maximal lethal concentration were calculatede. Wound-healing and transwell assays were performed to examine gastric cancer cell motility. Clonogenic assays were performed to investigate the synergistic effects of Cycas revoluta Thunb. with 5-Fu, and apoptotic bodies were detected by Hoechst staining. Western blotting was performed to examine the expression of related proteins and to investigate the molecular mechanism of Cycas revoluta Thunb.-induced cancer cell apoptosis. The expressions of proteins, including mammalian target of rapamycin (mTOR) and p-AKT, were detected in different combinations of treatments for 48 h, then analyzed by ECL detection.

RESULTS

Gastric cancer cells were more sensitive to the natural extract of Cycas revoluta Thunb. compared to normal gastric epithelial cells, and the extract effectively inhibited gastric cancer cell migration and invasion. The extract improved the anti-cancer effect of 5-Fu by enhancing the chemosensitization of gastric cancer cells. Extract plus 5-Fu further reduced the expression of the drug-resistance-related proteins p-AKT and mTOR after 48 h compared to 5-Fu alone. Compared to 5-Fu treatment alone, mTOR and p-AKT expression was significantly reduced by about 50% and 75%, respectively. We also found that the natural extract of Cycas revoluta Thunb. further increased 5-Fu-induced gastric cancer cell apoptosis. Expression of apoptosis-related protein X-linked inhibitor of apoptosis protein and apoptosis inducing factor were significantly reduced and increased, respectively, in the 5-Fu-resistant gastric cancer line SGC-7901/R treated with extract plus 5-Fu, while the expression of survivin did not change.

CONCLUSION

The natural extract of Cycas revoluta Thunb. effectively inhibited gastric cancer cell growth and enhanced the anti-cancer effect of 5-Fu through the AKT-mTOR pathway.

Keywords: Gastric cancer; 5-fluorouracil; Cycas revoluta Thunb.; Apoptosis

Core tip: 5-fluorouracil (5-Fu) is an effective treatment for gastric cancer, which is one of the most common and deadly malignancies worldwide. However, the effect of 5-Fu is limited by the drug resistance of gastric cancer. Here, we report that natural extract of Cycas revoluta Thunb. effectively inhibits gastric cancer cell growth, migration and invasion. Furthermore, it can be used in combination with 5-Fu to enhance its anti-cancer effects through the AKT-mTOR pathway.