Rondeau Justin D, Lipari Sara, Mathieu Barbara, Beckers Claire, Van de Velde Justine A, Mignion Lionel, Da Silva Morais Mauricio, Kreuzer Marvin, Colauzzi Ilaria, Capeloa Tania, Pruschy Martin, Gallez Bernard, Sonveaux Pierre
Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium.
Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute (LDRI), UCLouvain, Brussels, Belgium.
Cell Death Discov. 2024 Dec 27;10(1):514. doi: 10.1038/s41420-024-02277-9.
Hypoxic tumors are radioresistant stemming from the fact that oxygen promotes reactive oxygen species (ROS) propagation after water radiolysis and stabilizes irradiation-induced DNA damage. Therefore, an attractive strategy to radiosensitize solid tumors is to increase tumor oxygenation at the time of irradiation, ideally above a partial pressure of 10 mm-Hg at which full radiosensitization can be reached. Historically, the many attempts to increase vascular O delivery have had limited efficacy, but mathematical models predicted that inhibiting cancer cell respiration would be more effective. Here, we report that mitochondria-targeted antioxidant MitoQ can radiosensitize human breast tumors in mice. This was not a class effect, as neither MitoTEMPO nor SKQ1 shared this property. At clinically relevant nanomolar concentrations, MitoQ completely abrogated the oxygen consumption of several human cancer cell lines of different origins, which was associated with a glycolytic switch. Using orthotopic breast cancer models in mice, we observed that pretreating hypoxic MDA-MB-231 tumors with MitoQ delayed tumor growth with both single dose irradiation and clinically relevant fractionated radiotherapy. Oxygenated MCF7 tumors were not radiosensitized, suggesting an oxygen enhancement effect of MitoQ. Because MitoQ already successfully passed Phase I clinical trials, our findings foster its clinical evaluation in combination with radiotherapy.
缺氧肿瘤具有放射抗性，这是因为氧气在水辐射分解后会促进活性氧（ROS）的扩散，并使辐射诱导的DNA损伤稳定化。因此，使实体瘤对放疗敏感的一个有吸引力的策略是在放疗时增加肿瘤的氧合，理想情况下是在分压高于10毫米汞柱时，此时可以实现完全的放射增敏。从历史上看，许多增加血管氧输送的尝试效果有限，但数学模型预测抑制癌细胞呼吸会更有效。在这里，我们报告线粒体靶向抗氧化剂MitoQ可以使小鼠体内的人乳腺肿瘤对放疗敏感。这不是一种类效应，因为MitoTEMPO和SKQ1都不具有这种特性。在临床相关的纳摩尔浓度下，MitoQ完全消除了几种不同来源的人类癌细胞系的氧消耗，这与糖酵解转换有关。使用小鼠原位乳腺癌模型，我们观察到用MitoQ预处理缺氧的MDA-MB-231肿瘤，无论是单剂量照射还是临床相关的分割放疗，都能延迟肿瘤生长。含氧的MCF7肿瘤没有对放疗敏感，这表明MitoQ具有氧增强效应。由于MitoQ已经成功通过了I期临床试验，我们的研究结果促进了其与放疗联合的临床评估。
