Cheng Xianliang, Wang Guohui, Liao Yuan, Mo Jiao, Qing Chen
School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China.
Oncol Lett. 2020 Dec;20(6):281. doi: 10.3892/ol.2020.12144. Epub 2020 Sep 23.
13-Chlorine-3,15-dioxy-gibberellic acid methyl ester (GA-13315) is a gibberellin derivative that exhibits selective cytotoxicity to multidrug resistant MCF-7/ADR cells and reverses drug resistance when administered at subtoxic doses in combination with chemotherapy drugs. The present study aimed to investigate the impact of chronic GA-13315 exposure on the chemosensitivity of MCF-7 and HCT116 cell lines. Cells were administered a subtoxic dose of 1 µM GA-13315 for 12 weeks and the sensitivity of the cells to GA-13315, irinotecan and cisplatin, was assessed. The Cell Counting Kit-8 assay results demonstrated that the chronic exposure did not induce resistance to GA-13315, in either MCF-7 or HCT116 cells. Notably, MCF-7 cells were sensitized to irinotecan following exposure to GA-13315; however, HCT116 cells were not. The sensitizing effect of GA-13315 was associated with the alterations of topoisomerase 1 (Top1) protein expression, tyrosyl DNA phosphodiesterase 1 and checkpoint kinase 1. Further analysis indicated that GA-13315 caused DNA fragmentation; however, DNA damage was not mediated by a Top1-dependent molecular mechanism, as GA-13315 was revealed not to be a Top1 poison, despite inhibiting the catalytic activity of Top1. Taken together, the results of the present study indicated that GA-13315 may be used for sensitizing MCF-7 cells to irinotecan, as the chronic exposure of GA-13315 to MCF-7 cells still showed sensitizing effects to irinotecan.
13-氯-3,15-二氧代-赤霉素甲酯（GA-13315）是一种赤霉素衍生物，对多药耐药的MCF-7/ADR细胞具有选择性细胞毒性，并且在以亚毒性剂量与化疗药物联合给药时可逆转耐药性。本研究旨在探讨长期暴露于GA-13315对MCF-7和HCT116细胞系化学敏感性的影响。细胞接受1μM GA-13315的亚毒性剂量处理12周，并评估细胞对GA-13315、伊立替康和顺铂的敏感性。细胞计数试剂盒-8检测结果表明，长期暴露并未诱导MCF-7或HCT116细胞对GA-13315产生耐药性。值得注意的是，MCF-7细胞在暴露于GA-13315后对伊立替康敏感；然而，HCT116细胞并非如此。GA-13315的致敏作用与拓扑异构酶1（Top1）蛋白表达、酪氨酰DNA磷酸二酯酶1和检查点激酶1的改变有关。进一步分析表明，GA-13315导致DNA片段化；然而，DNA损伤并非由Top1依赖性分子机制介导，因为尽管GA-13315抑制Top1的催化活性，但它并非Top1毒物。综上所述，本研究结果表明，GA-13315可用于使MCF-7细胞对伊立替康敏感，因为GA-13315长期暴露于MCF-7细胞仍对伊立替康显示致敏作用。
