Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma Via Antagonizing Rad51-Mediated DNA-Repair

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Jan 12

PMID 26752698

Citations 11

Authors

Jinjin Shao

Zhifei Xu

Xueming Peng

Min Chen

Yuanrun Zhu

Li Xu

Hong Zhu

Bo Yang

Peihua Luo

Qiaojun He

Affiliations

Soon will be listed here.

Abstract

Chemotherapy is the only choice for most of the advanced hepatocellular carcinoma (HCC) patients, while few agents were available, making it an urgent need to develop new chemotherapy strategies. A phase II clinical trial suggested that the efficacy of irinotecan in HCC was limited due to dose-dependent toxicities. Here, we found that gefitinib exhibited synergistic activity in combination with SN-38, an active metabolite of irinotecan, in HCC cell lines. And the enhanced apoptosis induced by gefitinib plus SN-38 was a result from caspase pathway activation. Mechanistically, gefitinib dramatically promoted the ubiquitin-proteasome-dependent degradation of Rad51 protein, suppressed the DNA repair, gave rise to more DNA damages, and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of gefitinib combined with irinotecan was further validated in a HepG2 xenograft mice model. Taken together, our data demonstrated for the first time that the combination of irinotecan and gefitinib showed potential benefit in HCC, which suggests that Rad51 is a promising target and provides a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and gefitinib in HCC.

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