Abstract
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.