获得性耐药性是癌症治疗中的一个重大挑战，这强调了发现和开发新治疗策略的必要性。我们在这里报告了由稀土金属镨（Pr）和巯基吡啶氧化物（MPO；吡啶硫酮）组成的小配位配合物的抗癌活性机制。将癌细胞暴露于相对较低浓度的结合物 Pr-MPO (5 µM) 中，会以不依赖于 p53 的方式显着损害细胞存活，且与耐药表型无关。从机制上讲，Pr-MPO 诱导的细胞死亡是不依赖于 caspase 的，不能被 necrostatin 抑制，但与自噬标记物的出现有关。然而，进一步的分析揭示了不完全的自噬通量，从而表明溶酶体机器的完整性发生了改变。支持溶酶体靶向活性的数据表明，溶酶体 Ca2+ 积累和碱化增加，这与胞质酸化（pHc 从 7.75 降至 7.00）同时发生。与此同时，参与被动糖原分解的糖苷酶 α 酸 (GAA) 溶酶体活性的增加与 Pr-MPO 治疗后葡萄糖储备的快速消耗相关。这与 TCA 循环中间体的快速崩溃、NAD /NADH 的损失以及丙酮酸脱氢酶 (PDH) 活性的增加以补偿丙酮酸的损失有关。添加外源丙酮酸可挽救细胞存活。值得注意的是，Pr-MPO 引发的溶酶体损伤和代谢灾难表明存在 Zn2 介导的细胞毒性，Zn2 螯合剂 TPEN 阻断 Pr-MPO 介导的抗肿瘤活性的能力证实了这一点。总之，这些结果凸显了小分子镧系元素缀合物能够靶向细胞的废物清除机制以及 Zn2 介导的癌细胞执行的线粒体代谢，这可能具有针对高代谢活性癌症的治疗潜力。© 2024。作者。

Acquired drug resistance is a major challenge in the management of cancer, which underscores the need for discovery and development of novel therapeutic strategies. We report here the mechanism of the anti-cancer activity of a small coordinate complex composed of the rare earth metal praseodymium (Pr) and mercaptopyridine oxide (MPO; pyrithione). Exposure of cancer cells to relatively low concentrations of the conjugate Pr-MPO (5 µM) significantly impairs cell survival in a p53-independent manner and irrespective of the drug resistant phenotype. Mechanistically, Pr-MPO-induced cell death is caspase-independent, not inhibitable by necrostatin, but associated with the appearance of autophagy markers. However, further analysis revealed incomplete autophagic flux, thus suggesting altered integrity of lysosomal machinery. Supporting the lysosomal targeting activity are data demonstrating increased lysosomal Ca2+ accumulation and alkalinization, which coincides with cytosolic acidification (drop in pHc from 7.75 to 7.00). In parallel, an increase in lysosomal activity of glycosidase alpha acid (GAA), involved in passive glycogen breakdown, correlates with rapid depletion of glucose stores upon Pr-MPO treatment. This is associated with swift cataplerosis of TCA cycle intermediates, loss of NAD+/NADH and increase in pyruvate dehydrogenase (PDH) activity to compensate for pyruvate loss. Addition of exogenous pyruvate rescued cell survival. Notably, lysosomal impairment and metabolic catastrophe triggered by Pr-MPO are suggestive of Zn2+-mediated cytotoxicity, which is confirmed by the ability of Zn2+ chelator TPEN to block Pr-MPO-mediated anti-tumor activity. Together, these results highlight the ability of the small molecule lanthanide conjugate to target the cells' waste clearing machinery as well as mitochondrial metabolism for Zn2+-mediated execution of cancer cells, which could have therapeutic potential against cancers with high metabolic activity.© 2024. The Author(s).