PT-112 诱导线粒体应激和免疫原性细胞死亡，靶向具有线粒体缺陷的肿瘤细胞。,Cancers

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PT-112 诱导线粒体应激和免疫原性细胞死亡，靶向具有线粒体缺陷的肿瘤细胞。
Cancers ( IF 4.5 ) Pub Date : 2022-08-09 , DOI: 10.3390/cancers14163851
Ruth Soler-Agesta ₁ , Joaquín Marco-Brualla ₁ , Martha Minjárez-Sáenz _{1,

2} , Christina Y Yim ₃ , Marta Martínez-Júlvez _{1,

2} , Matthew R Price ₃ , Raquel Moreno-Loshuertos ₁ , Tyler D Ames ₃ , José Jimeno _{1,

3} , Alberto Anel ₁

Affiliation

PT-112 是一种新型焦磷酸-铂偶联物，据报道在晚期预处理实体瘤中具有临床活性。虽然 PT-112 已被证明可在体内诱导强烈的免疫原性细胞死亡 (ICD)，但仅与 DNA 结合的程度最低，但 PT-112 在癌细胞中靶向破坏的分子机制仍在阐明中。小鼠 L929 体外系统用于测试不同的代谢状态是否会改变 PT-112 的作用，包括细胞毒性。结果表明，与具有完整氧化磷酸化的亲本和杂种细胞相比，呈现线粒体 DNA (mtDNA) 突变并依赖糖酵解生存的肿瘤细胞对 PT-112 诱导的细胞死亡更敏感(OXPHOS) 途径（L929 和 dtL929 杂种细胞）。由 PT-112 诱导的细胞死亡类型不遵循经典的凋亡途径：通用半胱天冬酶抑制剂 Z-VAD-fmk 单独或与坏死性凋亡抑制剂 necrostatin-1 组合均不抑制 PT-112 诱导的细胞死亡。有趣的是，PT-112 在所有细胞系中都启动了自噬，尽管这个过程还没有完成。已知自噬与癌细胞中的综合应激反应和随后的 ICD 相关。PT-112 还诱导线粒体活性氧物质的大量积累，以及线粒体极化的变化——仅在具有线粒体功能障碍的敏感细胞中——以及与 ICD 一致的钙网蛋白细胞表面暴露。PT-112 显着降低了 L929 细胞中线粒体 CoQ10 的含量，而基础 CoQ10 水平低于我们在 L929dt 细胞中的检测限，表明 CoQ10 基础水平低与 PT-112 敏感性之间存在潜在关系。最后，与具有完整 OXPHOS 通路的细胞相比，对 PT-112 敏感的细胞中 HIF-1α 的表达要高得多，这表明潜在的临床应用。

"点击查看英文标题和摘要"

PT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies.

PT-112 is a novel pyrophosphate-platinum conjugate, with clinical activity reported in advanced pretreated solid tumors. While PT-112 has been shown to induce robust immunogenic cell death (ICD) in vivo but only minimally bind DNA, the molecular mechanism underlying PT-112 target disruption in cancer cells is still under elucidation. The murine L929 in vitro system was used to test whether differential metabolic status alters PT-112's effects, including cell cytotoxicity. The results showed that tumor cells presenting mutations in mitochondrial DNA (mtDNA) (L929dt and L929dt cybrid cells) and reliant on glycolysis for survival were more sensitive to cell death induced by PT-112 compared to the parental and cybrid cells with an intact oxidative phosphorylation (OXPHOS) pathway (L929 and dtL929 cybrid cells). The type of cell death induced by PT-112 did not follow the classical apoptotic pathway: the general caspase inhibitor Z-VAD-fmk did not inhibit PT-112-induced cell death, alone or in combination with the necroptosis inhibitor necrostatin-1. Interestingly, PT-112 initiated autophagy in all cell lines, though this process was not complete. Autophagy is known to be associated with an integrated stress response in cancer cells and with subsequent ICD. PT-112 also induced a massive accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial polarization-only in the sensitive cells harboring mitochondrial dysfunction-along with calreticulin cell-surface exposure consistent with ICD. PT-112 substantially reduced the amount of mitochondrial CoQ10 in L929 cells, while the basal CoQ10 levels were below our detection limits in L929dt cells, suggesting a potential relationship between a low basal level of CoQ10 and PT-112 sensitivity. Finally, the expression of HIF-1α was much higher in cells sensitive to PT-112 compared to cells with an intact OXPHOS pathway, suggesting potential clinical applications.

更新日期：2022-08-09

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