Briehl Margaret M, Tome Margaret E, Wilkinson Sarah T, Jaramillo Melba C, Lee Kristy
*Department of Pathology, University of Arizona, P.O. Box 24-5043, Tucson, AZ 85724-5043, U.S.A.
†Department of Medical Pharmacology, University of Arizona, P.O. Box 24-5050, Tucson, AZ 85724-5050, U.S.A.
Biochem Soc Trans. 2014 Aug;42(4):939-44. doi: 10.1042/BST20140087.
Characteristics of cancer cells include a more oxidized redox environment, metabolic reprogramming and apoptosis resistance. Our studies with a lymphoma model have explored connections between the cellular redox environment and cancer cell phenotypes. Alterations seen in lymphoma cells made resistant to oxidative stress include: a more oxidized redox environment despite increased expression of antioxidant enzymes, enhanced net tumour growth, metabolic changes involving the mitochondria and resistance to the mitochondrial pathway to apoptosis. Of particular importance, the cells show cross-resistance to multiple chemotherapeutic agents used to treat aggressive lymphomas. Analyses of clinical and tumour data reveal the worst prognosis when patients' lymphomas have gene expression patterns consistent with the most oxidized redox environment. Lymphomas from patients with the worst survival outcomes express increased levels of proteins involved in oxidative phosphorylation, including cytochrome c. This is consistent with these cells functioning as metabolic opportunists. Using lymphoma cell models and primary lymphoma cultures, we observed enhanced killing using genetic and drug approaches which further oxidize the cellular redox environment. These approaches include increased expression of SOD2 (superoxide dismutase 2), treatment with a manganoporphyrin that oxidizes the glutathione redox couple, or treatment with a copper chelator that inhibits SOD1 and leads to peroxynitrite-dependent cell death. The latter approach effectively kills lymphoma cells that overexpress the anti-apoptotic protein Bcl-2. Given the central role of mitochondria in redox homoeostasis, metabolism and the intrinsic pathway to apoptosis, our studies support the development of new anti-cancer drugs to target this organelle.
癌细胞的特征包括氧化还原环境更加氧化、代谢重编程和抗凋亡能力。我们对淋巴瘤模型的研究探索了细胞氧化还原环境与癌细胞表型之间的联系。在对氧化应激产生抗性的淋巴瘤细胞中观察到的变化包括：尽管抗氧化酶表达增加，但氧化还原环境更加氧化、肿瘤净生长增强、涉及线粒体的代谢变化以及对线粒体凋亡途径的抗性。特别重要的是，这些细胞对用于治疗侵袭性淋巴瘤的多种化疗药物表现出交叉抗性。对临床和肿瘤数据的分析表明，当患者的淋巴瘤具有与最氧化的氧化还原环境一致的基因表达模式时预后最差。生存结果最差的患者的淋巴瘤中，参与氧化磷酸化的蛋白质（包括细胞色素c）表达水平升高。这与这些细胞作为代谢机会主义者的功能一致。使用淋巴瘤细胞模型和原发性淋巴瘤培养物，我们观察到通过遗传和药物方法进一步氧化细胞氧化还原环境可增强杀伤作用。这些方法包括增加超氧化物歧化酶2（SOD2）的表达、用氧化谷胱甘肽氧化还原对的锰卟啉处理，或用抑制SOD1并导致过氧亚硝酸盐依赖性细胞死亡的铜螯合剂处理。后一种方法有效地杀死了过度表达抗凋亡蛋白Bcl-2的淋巴瘤细胞。鉴于线粒体在氧化还原稳态、代谢和凋亡内在途径中的核心作用，我们的研究支持开发针对该细胞器的新型抗癌药物。
