Identification of a novel potential antitumor activity of gossypol as an APE1/Ref-1 inhibitor.
Identification of a novel potential antitumor activity of gossypol as an APE1/Ref-1 inhibitor.
复制标题
DOI：
10.2147/dddt.s62963
复制
发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Qian C;Li M;Sui J;Ren T;Li Z;Zhang L;Zhou L;Cheng Y;Wang D
人APE1/ redox增强因子-1 （APE1/ ref1）是一种参与氧化脱氧核糖核酸（DNA）损伤修复和转录调控的重要多功能蛋白，在肿瘤组织和癌细胞中经常过表达。此外，APE1/Ref-1 （APE1）过表达与人类肿瘤的化疗耐药有关。因此，抑制癌细胞中的APE1功能被认为是克服对治疗剂耐药的一种有希望的策略。棉酚是一种Bcl-2同源3 （BH3）模拟剂，能够结合到b细胞淋巴瘤2 （Bcl-2）家族成员的BH3结构域。其他研究表明，Bcl-2通过其BH结构域直接与APE1相互作用。通过apurinic/apyrimidinic （AP）核酸内切酶测定，我们发现棉酚抑制APE1的修复活性。电泳迁移率转移实验和双荧光素酶实验表明，棉酚还能抑制APE1的氧化还原功能。利用双偏振干涉技术，我们发现棉酚可以直接与APE1相互作用。此外，棉酚的添加与APE1的过表达一起导致癌细胞死亡。棉酚的加入也增强了实验室烷基化剂甲磺酸甲酯和临床药物顺铂（DDP）的细胞杀伤效果。棉酚能显著抑制异种移植物的生长。此外，棉酚和DDP联合治疗在体内的抗肿瘤活性比单独使用DDP有统计学意义上更高。总之，我们已经证明棉酚通过直接相互作用有效地抑制APE1的修复和氧化还原活性。
The human apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (APE1/Ref-1), an essential multifunctional protein involved in the repair of oxidative deoxyribonucleic acid (DNA) damage and transcriptional regulation, is often overexpressed in tumor tissues and cancer cells. Moreover, APE1/Ref-1 (APE1) overexpression has been linked to chemoresistance in human tumors. Thus, inhibiting APE1 function in cancer cells is considered a promising strategy to overcome resistance to therapeutic agents. Gossypol is a Bcl-2 homology 3 (BH3)-mimetic agent and is able to bind to the BH3 domain of B-cell lymphoma 2 (Bcl-2) family members. Other studies demonstrated that Bcl-2 directly interacted with APE1 via its BH domains. Using apurinic/apyrimidinic (AP) endonuclease assays, we found that gossypol inhibits the repair activity of APE1. Electrophoretic mobility shift assays and dual luciferase assays showed that gossypol could also inhibit the redox function of APE1. Using dual polarization interferometry technology, we show that gossypol can directly interact with APE1. Furthermore, addition of gossypol, in conjunction with APE1 overexpression, leads to cancer cell death. The addition of gossypol also enhances the cell killing effect of the laboratory alkylating agent methyl methanesulfonate and the clinical agent cisplatin (DDP). Administration of gossypol significantly inhibited the growth of xenografts. Furthermore, the combined treatment of gossypol and DDP resulted in a statistically higher antitumor activity compared with DDP alone in vivo. In conclusion, we have demonstrated that gossypol effectively inhibits the repair and redox activity of APE1 through a direct interaction.