Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2016; 22(32): 7342-7352
Published online Aug 28, 2016. doi: 10.3748/wjg.v22.i32.7342
Synergistic anticancer effect of exogenous wild-type p53 gene combined with 5-FU in human colon cancer resistant to 5-FU in vivo
Qi Xie, Min-Yi Wu, Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Jing Zhang, Jin Xu, Wei-De Zhong, Jia-Ni Hu
Qi Xie, Min-Yi Wu, Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China
Jing Zhang, Department of Pathology, Cancer Center, SunYat-sen University, Guangzhou 510080, Guangdong Province, China
Jin Xu, Department of Pathology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 510180, Guangdong Province, China
Wei-De Zhong, Clinical Molecular Medicine and Molecular Diagnostics Laboratory, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 510180, Guangdong Province, China
Jia-Ni Hu, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States
Author contributions: Xie Q designed the study; Wu MY, Zhang DX and Yang YM performed the research; Zhang J and Xu J collected and analyzed the data; Wang BS performed the MRI; Zhong WD conducted the statistical analysis; Xie Q and Zhang DX wrote the manuscript;Hu JN revised the manuscript.
Supported by the Natural Science Foundation of Guangdong, No. 2015A030313732.
Institutional review board statement: The study was reviewed and approved by the Experimental Animal Center of Sun Yat-sen University and Guangzhou Medical University respectively.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University and Guangzhou Medical University.
Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at xieqi8@yeah.net.
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: Qi Xie, MD, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China. xieqi8@yeah.net
Telephone: +86-20-22903628 Fax: +86-20-22903699
Received: April 23, 2016
Peer-review started: April 23, 2016
First decision: May 27, 2016
Revised: June 11, 2016
Accepted: July 6, 2016
Article in press: July 6, 2016
Published online: August 28, 2016
Processing time: 122 Days and 22.8 Hours
Abstract
AIM

To investigate the anticancer effect of a recombinant adenovirus-mediated p53 (rAd-p53) combined with 5-fluorouracil (5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of rAd-p53 in reversal of 5-FU resistance.

METHODS

Nude mice bearing human colon cancer SW480/5-FU (5-FU resistant) were randomly assigned to four groups (n = 25 each): control group, 5-FU group, rAd-p53 group, and rAd-p53 + 5-FU group. At 24 h, 48 h, 72 h, 120 h and 168 h after treatment, 5 mice were randomly selected from each group and sacrificed using an overdose of anesthetics. The tumors were removed and the protein expressions of p53, protein kinase C (PKC), permeability-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) (Western blot) and apoptosis (TUNEL) were determined.

RESULTS

The area ratios of tumor cell apoptosis were larger in the rAd/p53 + 5-FU group than that in the control, 5-FU and rAd/p53 groups (P < 0.05), and were larger in the rAd/p53 group than that of the control group (P < 0.05) and the 5-FU group at more than 48 h (P < 0.05). The p53 expression was higher in the rAd/p53 and the rAd/p53 + 5-FU groups than that of the control and 5-FU groups (P < 0.05), and were higher in the rAd/p53 + 5-FU group than that of the rAd/p53 group (P < 0.05). Overexpression of PKC, P-gp and MRP1 was observed in the 5-FU and control groups. In the rAd/p53 + 5-FU group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups (P < 0.05), and the expression of PKC was lower than that of the control, 5-FU and rAd/p53 groups at more than 48 h (P < 0.05). In the rAd/p53 group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups at more than 48 h (P < 0.05), and the expression of PKC was lower than that of the control and 5-FU groups at more than 120 h (P < 0.05).

CONCLUSION

5-FU combined with rAd-p53 has a synergistic anticancer effect in SW480/5-FU (5-FU resistance), which contributes to reversal of 5-FU resistance.

Keywords: Human colon cancer; Multidrug resistance; 5-Fluorouracil; Recombinant adenovirus-mediated p53; Xenografts in nude mice

Core tip: To observe anticancer action of a recombinant adenovirus-mediated p53 (rAd-p53) combined with 5-fluorouracil (5-FU) in human colon cancer with resistance to 5-FU in vivo to investigate the potential and mechanism of rAd-p53 in the reversal of resistance to 5-FU in human colon cancer. Our previous results revealed that exogenous wild-type p53 gene from rAd-p53 can decrease expression of PKC, P-gp and MRP1 in SW480/5-FU (5-FU resistance) and promote apoptosis of tumor cell, which contributes to reversing 5-FU resistance in vivo. 5-FU can increase the expression of exogenous wild-type p53, so 5-FU combined with rAd-p53 has a synergistic anticancer effect for colon cancer of 5-FU resistance in vivo.