Oxidative stress induced by the tetrahydrobenzimidazole TMQ0153 modulates crosstalk between apoptosis, autophagy and necroptosis in chronic myeloid leukemia - Part 2 (Figure2, 3, 4)

Aims: We demonstrate the capacity of the cytotoxic synthetic tetrahydrobenzimidazole (TMQ) hydroquinone (HQ) derivative TMQ0153 to induce reactive oxygen species (ROS) and mediate differential cell death modalities in chronic myeloid leukemia (CML). Results: Results showed that concentrations of TMQ0153 < 20 µM trigger apoptosis, whereas concentrations > 30 µM lead to ROS-mediated necrostatin-sensitive necroptosis. Moreover, TMQ0153 allowed us to elucidate the interplay of ROS-mediated cell death and cell stress/survival mechanisms as this compound triggers protective autophagy in response to metabolic stress in CML cells. Importantly, the modulation of cell stress prior to TMQ0153-induced cell death enhances the exposure of “find-me”/“eat-me” signals considered as hallmarks of immunogenic cell death (ICD), altogether providing a pro-oxidant therapeutic strategy against CML. Innovation: We suggest here a pro-oxidant anti-CML therapy leading to differential cell death modalities in both imatinib-sensitive and -resistant CML cell types. Moreover, we elucidated the interplay between apoptosis, autophagy and controlled necrosis induced by TMQ0153 leading to disruption of mitochondrial homeostasis. Conclusion: Our findings indicate that TMQ0153-induced ROS act as a rheostat determining the onset of apoptotic- or autophagy-related controlled necrotic cell death in CML.

研究目标：本研究旨在证明细胞毒性合成四氢苯并咪唑（tetrahydrobenzimidazole, TMQ）氢醌（hydroquinone, HQ）衍生物TMQ0153可诱导活性氧（reactive oxygen species, ROS）生成，并介导慢性髓系白血病（chronic myeloid leukemia, CML）细胞发生不同类型的细胞死亡方式。
研究结果：结果显示，当TMQ0153浓度低于20 μM时可诱导细胞凋亡，而浓度高于30 μM时则会引发ROS介导的、可被坏死抑素（necrostatin）阻断的坏死性凋亡。此外，TMQ0153可帮助我们阐明ROS介导的细胞死亡与细胞应激/存活机制之间的相互作用：该化合物可在慢性髓系白血病细胞中触发保护性自噬以应对代谢应激。值得注意的是，在TMQ0153诱导细胞死亡前对细胞应激进行调控，可增强被视为免疫原性细胞死亡（immunogenic cell death, ICD）标志性特征的“find-me”/“eat-me”信号的暴露，进而为慢性髓系白血病提供一种促氧化治疗策略。
创新点：本研究提出一种针对慢性髓系白血病的促氧化抗白血病疗法，可在伊马替尼（imatinib）敏感型与耐药型慢性髓系白血病细胞中均诱导产生不同的细胞死亡模式。此外，我们阐明了TMQ0153诱导的细胞凋亡、自噬与受控性坏死之间的相互调控关系，该过程可破坏线粒体稳态（mitochondrial homeostasis）。
研究结论：本研究结果表明，TMQ0153诱导产生的ROS可作为一种调控变阻器，决定慢性髓系白血病细胞发生凋亡相关或自噬相关的受控性坏死性细胞死亡。