Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair.
Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair.
复制标题
吉非替尼与伊立替康协同作用，通过拮抗 Rad51 介导的 DNA 修复来抑制肝细胞癌
DOI：
10.1371/journal.pone.0146968
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
He Q
中科院分区：
文献类型：
--
作者：
Shao J;Xu Z;Peng X;Chen M;Zhu Y;Xu L;Zhu H;Yang B;Luo P;He Q
化疗是大多数晚期肝细胞癌（HCC）患者的唯一选择，但目前可用的化疗药物较少，迫切需要开发新的化疗策略。一项II期临床试验表明，由于剂量依赖性毒性，伊立替康在HCC中的疗效有限。在这里，我们发现吉非替尼与SN-38（伊立替康的活性代谢物）联合在HCC细胞系中表现出协同活性。吉非替尼联合SN-38诱导的细胞凋亡增强是caspase途径激活的结果。在机制上，吉非替尼显著促进了Rad 51蛋白的泛素-蛋白酶体依赖性降解，抑制了DNA修复，导致更多的DNA损伤，最终导致两种药物的协同作用。此外，在HepG 2异种移植小鼠模型中进一步验证了吉非替尼联合伊立替康的抗肿瘤疗效增加。综上所述，我们的数据首次证明了伊立替康和吉非替尼的组合在HCC中显示出潜在的益处，这表明Rad 51是一个有希望的靶点，并为研究拓扑异构酶I抑制剂和吉非替尼组合在HCC中的疗效的临床试验提供了理论基础。
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.