Sui Hongying, Shi Caixia, Yan Zhipeng, Li Hucheng
Department of Gynecological Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha City, People's Republic of China.
Drug Des Devel Ther. 2015 Jun 22;9:3183-90. doi: 10.2147/DDDT.S82035. eCollection 2015.
Ovarian cancer is the leading cause of death in women with gynecological malignancy worldwide. Despite multiple new approaches to treatment, relapse remains almost inevitable in patients with advanced disease. The poor outcome of advanced ovarian cancer treated with conventional therapy stimulated the search for new strategies to improve therapeutic efficacy. Although epidermal growth factor receptor (EGFR) and poly(ADP-ribose) polymerase (PARP) inhibitors have known activity in advanced ovarian cancer, the effect of combined therapy against EGFR and PARP in this population has not been reported. In the current study, we investigated the mechanisms of erlotinib used alone or in combination with olaparib (AZD2281), a potent inhibitor of PARP, in an EGFR-overexpressing ovarian tumor xenograft model.
A2780 (EGFR-overexpressing, BRCA1/2 wild-type) cells were subcutaneously injected into nude mice, which were then randomly assigned to treatment with vehicle, erlotinib, AZD2281, or erlotinib + AZD2281, for up to 3 weeks. All mice were then sacrificed and tumor tissues were subjected to Western blot analysis and monodansylcadervarine staining (for analysis of autophagy).
Erlotinib could slightly inhibit growth of A2780 tumor xenografts, and AZD2281 alone had similar effects on tumor growth. However, the combination treatment had a markedly enhanced antitumor effect. Western blot analysis revealed that treatment with erlotinib could significantly reduce the phosphorylation level of ERK1/2 and AKT in A2780 tumor tissue. Of interest, monodansylcadervarine staining showed that the autophagic effects were substantially enhanced when the agents were combined, which may be due to downregulation of apoptosis.
These results suggest that combination of a selective EGFR inhibitor and a PARP inhibitor is effective in ovarian cancer A2780 xenografts, and depends on enhanced autophagy.
卵巢癌是全球妇科恶性肿瘤女性患者的主要死因。尽管有多种新的治疗方法，但晚期疾病患者几乎不可避免地会复发。传统疗法治疗晚期卵巢癌的不良结局促使人们寻找提高治疗效果的新策略。虽然表皮生长因子受体（EGFR）和聚（ADP - 核糖）聚合酶（PARP）抑制剂在晚期卵巢癌中具有已知活性，但联合治疗EGFR和PARP在该人群中的效果尚未见报道。在本研究中，我们在EGFR过表达的卵巢肿瘤异种移植模型中研究了厄洛替尼单独使用或与PARP强效抑制剂奥拉帕尼（AZD2281）联合使用的机制。
将A2780（EGFR过表达、BRCA1/2野生型）细胞皮下注射到裸鼠体内，然后将裸鼠随机分为接受载体、厄洛替尼、AZD2281或厄洛替尼 + AZD2281治疗，持续3周。然后处死所有小鼠，对肿瘤组织进行蛋白质印迹分析和单丹磺酰尸胺染色（用于自噬分析）。
厄洛替尼可轻微抑制A2780肿瘤异种移植瘤的生长，单独使用AZD2281对肿瘤生长有类似作用。然而，联合治疗具有显著增强的抗肿瘤作用。蛋白质印迹分析显示，厄洛替尼治疗可显著降低A2780肿瘤组织中ERK1/2和AKT的磷酸化水平。有趣的是，单丹磺酰尸胺染色显示，联合使用这些药物时自噬作用显著增强，这可能是由于细胞凋亡下调所致。
这些结果表明，选择性EGFR抑制剂和PARP抑制剂联合使用对卵巢癌A2780异种移植瘤有效，且依赖于增强的自噬作用。
