title: Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair.
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.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Shao
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xueming
authors.initials: X
authors.lastname: Peng
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yuanrun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Peihua
authors.initials: P
authors.lastname: Luo
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D000077156:Gefitinib; D056945:Hep G2 Cells; D006801:Humans; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D034741:RNA, Small Interfering; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D000077156:Gefitinib; D002166:Camptothecin