Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, 80756, Taiwan.
Arch Toxicol. 2024 May;98(5):1543-1560. doi: 10.1007/s00204-024-03699-1. Epub 2024 Feb 29.
Excavatolide C (EXCC), a marine coral-derived compound, exhibits an antiproliferation effect on bladder cancer cells. The present study evaluated the improvement in the antiproliferation ability of EXCC by co-treatment with cisplatin in bladder cancer cells. EXCC/cisplatin (12.5 and 1 μg/mL) showed higher antiproliferation effects on bladder cancer cells than single treatments (EXCC or cisplatin alone) in the 48 h ATP assay. EXCC/cisplatin also enhanced the increase in subG1, annexin V-mediated apoptosis, and activation of poly (ADP-ribose) polymerase (PARP) and several caspases (caspases 3, 8, and 9) compared to the single treatments. Cellular and mitochondrial oxidative stress was enhanced with EXCC/cisplatin compared to the single treatments according to analyses of reactive oxygen species (ROS), mitochondrial superoxide, and mitochondrial membrane potential; in addition, cellular antioxidants, such as glutathione (GSH), and the mRNA expressions of antioxidant signaling genes (catalase and NFE2-like bZIP transcription factor 2) were downregulated. EXCC/cisplatin treatment produced more DNA damage than the single treatments, as indicated by γH2AX and 8-hydroxy-2'-deoxyguanosine levels. Moreover, several DNA repair genes for homologous recombination (HR) and non-homologous end joining (NHEJ) were downregulated in EXCC/cisplatin compared to others. The addition of the GSH precursor N-acetylcysteine, which has ROS scavenging activity, attenuated all EXCC/cisplatin-induced changes. Notably, EXCC/cisplatin showed lower antiproliferation, apoptosis, ROS induction, GSH depletion, and γH2AX DNA damage in normal cells than in bladder cancer cells. Therefore, the co-treatment of EXCC/cisplatin reduces the proliferation of bladder cancer cells via oxidative stress-mediated mechanisms with normal cell safety.
挖掘菌素 C (EXCC) 是一种来源于海洋珊瑚的化合物，对膀胱癌细胞具有抗增殖作用。本研究评估了 EXCC 与顺铂联合治疗对膀胱癌细胞抗增殖能力的改善作用。在 48 小时 ATP 测定中，EXCC/顺铂（12.5 和 1μg/mL）对膀胱癌细胞的抗增殖作用高于单独用药（EXCC 或顺铂）。与单独用药相比，EXCC/顺铂还增强了亚 G1 期、膜联蛋白 V 介导的细胞凋亡以及多聚（ADP-核糖）聚合酶 (PARP) 和几种半胱天冬酶 (caspase 3、8 和 9) 的激活。与单独用药相比，根据活性氧 (ROS)、线粒体超氧化物和线粒体膜电位的分析，EXCC/顺铂增强了细胞和线粒体氧化应激；此外，细胞抗氧化剂如谷胱甘肽 (GSH) 和抗氧化信号基因 (过氧化氢酶和 NFE2 样 bZIP 转录因子 2) 的 mRNA 表达下调。与单独用药相比，EXCC/顺铂处理产生的 DNA 损伤更多，如 γH2AX 和 8-羟基-2'-脱氧鸟苷水平所示。此外，与其他药物相比，同源重组 (HR) 和非同源末端连接 (NHEJ) 的几种 DNA 修复基因在 EXCC/顺铂中下调。添加具有 ROS 清除活性的 GSH 前体 N-乙酰半胱氨酸可减弱 EXCC/顺铂引起的所有变化。值得注意的是，与膀胱癌细胞相比，EXCC/顺铂在正常细胞中表现出较低的抗增殖、凋亡、ROS 诱导、GSH 耗竭和 γH2AX DNA 损伤。因此，EXCC/顺铂的联合治疗通过具有正常细胞安全性的氧化应激介导机制降低膀胱癌细胞的增殖。
