线粒体抗氧化剂mitoquinone改变癌细胞对治疗的死亡结局

Background: Cell death resistant cancer cells are challenging to treat with existing therapies and are major drivers of recurrence, morbidity, and mortality. Novel cell death-modulating drugs show promise for enhancing the therapeutic efficacy of first-line chemotherapeutic agents and may potentially improve patient outcomes. Both apoptosis and ferroptosis sensitivities are known to be modulated by changes in the redox environment from excessive oxidative stress, however, the mechanisms that determine cell commitment to each form of cell death are unclear. Therefore, to investigate how cell death outcomes might be adapted by changes to the cellular redox environment we used the mitochondrial antioxidant Mitoquinone (MitoQ) as a tool compound to dissect differences between apoptosis and ferroptosis outcomes in response to chemotherapeutic agents. Methods: Wild-type and BAX -/- BAK -/- HeLa (human cervical cancer) cells, as well as B16-F10 (metastatic murine melanoma) wild-type cells were treated with MitoQ (0.1-1 µM) alone or in combination with either an apoptosis-inducing cocktail of BH3 mimetics (1 µM ABT-263 + 1 µM S63845) or a ferroptosis-inducing cocktail (1 µM RSL3 + 1 µM Erastin2). Inhibitors of apoptosis (Q-VD-OPh) and ferroptosis (Ferrostatin-1) were used as controls to confirm the cell death modality. After 48 hours, cell viability and stage of cell death were assessed by flow cytometry using TMRE staining, CellEvent Green Caspase 3/7 Reporter, Annexin V, and DAPI to detect mitochondrial outer membrane permeabilization, caspase activation, phosphatidylserine externalization and plasma membrane permeabilization, respectively. Results: In wild-type cancer cell lines, increasing MitoQ concentrations (doses up to 0.3 μM) enhanced the induction of apoptosis in response to BH3 mimetics but suppressed ferroptosis induction in response to GPX4/System xc - inhibition. Across all three cell lines, treatment with high doses of single-agent MitoQ (1 µM and above) induced a significant increase in cell death, even in BAX/BAK-deficient cells. Conclusion: These findings suggest that modulation of mitochondrial oxidative stress via MitoQ modulates cancer cell death outcomes, promoting apoptosis while suppressing ferroptosis at low doses. Further work is needed to elucidate the molecular mechanisms underlying these effects and their implications for modulating cancer cell death modalities to improve cancer therapy outcomes.