Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
National Institute of Pharmaceutical Education and Research, Mohali, India.
IUBMB Life. 2024 Dec;76(12):1186-1198. doi: 10.1002/iub.2899. Epub 2024 Jul 22.
Estramustine (EM), a clinically successful hormone-refractory anti-prostate cancer drug, exhibited potent anti-proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH-SY5Y and IMR-32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre-treatment of neuroblastoma cells with ROS scavengers (N-acetyl cysteine and dithiothreitol) reduced the anti-proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin-1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule-depolymerizing agents may be considered for developing pro-ferroptosis chemotherapeutics.
依托泊苷（EM）是一种临床上成功的抗激素难治性前列腺癌药物，具有很强的抗增殖活性，可解聚微管、阻止细胞有丝分裂，并诱导不同癌细胞死亡。改变铁代谢是癌细胞的一个特征。我们使用 EM 研究了微管解聚和诱导人神经母细胞瘤（SH-SY5Y 和 IMR-32）细胞发生铁死亡之间的可能关系。EM 降低了谷胱甘肽（GSH）水平并诱导了活性氧（ROS）的产生。神经母细胞瘤细胞用 ROS 清除剂（N-乙酰半胱氨酸和二硫苏糖醇）预处理可降低 EM 的抗增殖作用。EM 处理增加了不稳定铁池（LIP），耗竭了谷胱甘肽过氧化物酶 4（GPX4）水平并发生脂质过氧化，这是铁死亡的标志性特征，突出了铁死亡的诱导。铁死亡抑制剂（甲磺酸去铁胺和 liproxstatin-1）阻断了 EM 的细胞毒性作用，进一步证实了铁死亡的诱导。长春花碱和诺考达唑也增加了 LIP 并诱导了神经母细胞瘤细胞的脂质过氧化。这项研究为微管完整性与铁死亡的偶联提供了证据。结果还表明，微管解聚剂可用于开发促铁死亡的化疗药物。
