Liu Yongqing, Yue Chunwen, Li Juan, Wu Jing, Wang Shikang, Sun Deqing, Guo Yanxia, Lin Zhaomin, Zhang Denglu, Wang Rongmei
Department of Pharmacy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.
Department of Emergency Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
Oncol Lett. 2018 Mar;15(3):2871-2880. doi: 10.3892/ol.2017.7664. Epub 2017 Dec 20.
Retigeric acid B (RAB), a natural compound isolated from lichen, has been demonstrated to inhibit cell growth and promote apoptosis in prostate cancer (PCa) cells. The present study evaluated the function of RAB combined with clinical chemotherapeutic drugs in PCa cell lines by MTT assay, reverse transcription quantitative polymerase chain reaction and western blot analysis, and identified that RAB at low doses produced significant synergistic cytotoxicity in combination with cisplatin (CDDP); however, no marked synergism between RAB and the other chemotherapeutics was observed. Additional studies revealed that RAB exerted an inhibitory effect on DNA damage repair pathways, including the nucleotide excision repair and mismatch repair pathways, which are involved in the sensitivity to CDDP-based chemotherapy, as suggested by the significantly downregulated expression of certain associated repair proteins. Notably, Excision repair cross-complementing 1, a critical gene in the nucleotide excision repair pathway, exhibited the most significant decrease. When combined with CDDP, RAB-mediated impairment of DNA repair resulted in prolonged DNA damage, as demonstrated by the long-lasting appearance of phosphorylation of histone H2AX at Ser139, which potentially enhanced the chemosensitivity to CDDP. Concurrently, the proapoptotic protein death receptor 5 (DR5) was activated by RAB, which also enhanced the chemotherapeutic response of CDDP. Knockdown of DR5 partially blocked RAB-CDDP synergism, suggesting the crucial involvement of DR5 in this event. The results of the present study identified that RAB functioned synergistically with CDDP to increase the efficacy of CDDP by inhibiting DNA damage repair and activating DR5, suggesting the mechanistic basis for the antitumor effect of RAB in combination with current chemotherapeutics.
瑞替吉酸B（RAB）是一种从地衣中分离出的天然化合物，已被证明可抑制前列腺癌细胞（PCa）的生长并促进其凋亡。本研究通过MTT法、逆转录定量聚合酶链反应和蛋白质免疫印迹分析评估了RAB与临床化疗药物联合在PCa细胞系中的作用，发现低剂量的RAB与顺铂（CDDP）联合可产生显著的协同细胞毒性；然而，未观察到RAB与其他化疗药物之间有明显的协同作用。进一步研究表明，RAB对DNA损伤修复途径具有抑制作用，包括核苷酸切除修复和错配修复途径，这些途径与基于CDDP的化疗敏感性有关，某些相关修复蛋白的表达显著下调表明了这一点。值得注意的是，核苷酸切除修复途径中的关键基因切除修复交叉互补蛋白1的表达下降最为显著。与CDDP联合时，RAB介导的DNA修复损伤导致DNA损伤延长，这表现为组蛋白H2AX在Ser139处磷酸化的持续出现，这可能增强了对CDDP的化学敏感性。同时，RAB激活了促凋亡蛋白死亡受体5（DR5），这也增强了CDDP的化疗反应。敲低DR5可部分阻断RAB-CDDP的协同作用，表明DR5在此过程中起关键作用。本研究结果表明，RAB与CDDP协同作用，通过抑制DNA损伤修复和激活DR5来提高CDDP的疗效，这为RAB与现有化疗药物联合抗肿瘤作用提供了机制基础。
