Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
FEBS Open Bio. 2020 May;10(5):789-801. doi: 10.1002/2211-5463.12830. Epub 2020 Apr 14.
The hypoxic environment within solid tumors impedes the efficacy of chemotherapeutic treatments. Here, we demonstrate that hypoxia augments the capacity of melanoma cells to withstand cisplatin and doxorubicin cytotoxicity. We show that B16F10 cells derived from spontaneously formed melanoma and YUMM1.7 cells, engineered to recapitulate human-relevant melanoma driver mutations, profoundly differ in their vulnerabilities to cisplatin and doxorubicin. The differences are manifested in magnitude of proliferative arrest and cell death rates, extent of mtDNA depletion, and impairment of mitochondrial respiration. In both models, cytotoxicity is mitigated by hypoxia, which augments glycolytic metabolism. Collectively, the findings implicate metabolic reprogramming in drug evasion and suggest that melanoma tumors with distinct genetic makeup may have differential drug vulnerabilities, highlighting the importance of precision anticancer treatments.
实体瘤中的缺氧环境会阻碍化疗治疗的效果。在这里，我们证明了缺氧会增强黑色素瘤细胞耐受顺铂和阿霉素细胞毒性的能力。我们发现，源自自发性黑色素瘤的 B16F10 细胞和 YUMM1.7 细胞在对顺铂和阿霉素的敏感性方面存在显著差异，YUMM1.7 细胞是为了重现人类相关的黑色素瘤驱动突变而设计的。这些差异表现在增殖抑制和细胞死亡率的幅度、线粒体 DNA 耗竭的程度以及线粒体呼吸的损伤。在这两种模型中，缺氧都会减轻细胞毒性，同时增强糖酵解代谢。总的来说，这些发现表明代谢重编程在药物逃避中起作用，并提示具有不同遗传构成的黑色素瘤肿瘤可能具有不同的药物敏感性，这突出了精准抗癌治疗的重要性。
