Primary tumors evolve metabolic mechanisms favoring glycolysis for adenosine triphosphate (ATP) generation and antioxidant defenses. In contrast, metastatic cells frequently depend on mitochondrial respiration and oxidative phosphorylation (OxPhos). This reliance of metastatic cells on OxPhos can be exploited using drugs that target mitochondrial metabolism. Therefore, therapeutic agents that act via diverse mechanisms, including the activation of signaling pathways that promote the production of reactive oxygen species (ROS) and/or a reduction in antioxidant defenses may elevate oxidative stress and inhibit tumor cell survival. In this review, we will provide (1) a mechanistic analysis of function-selective extracellular signal-regulated kinase-1/2 (ERK1/2) inhibitors that inhibit cancer cells through enhanced ROS, (2) a review of the role of mitochondrial ATP synthase in redox regulation and drug resistance, (3) a rationale for inhibiting ERK signaling and mitochondrial OxPhos toward the therapeutic goal of reducing tumor metastasis and treatment resistance. Recent reports from our laboratories using metastatic melanoma and breast cancer models have shown the preclinical efficacy of novel and rationally designed therapeutic agents that target ERK1/2 signaling and mitochondrial ATP synthase, which modulate ROS events that may prevent or treat metastatic cancer. These findings and those of others suggest that targeting a tumor's metabolic requirements and vulnerabilities may inhibit metastatic pathways and tumor growth. Approaches that exploit the ability of therapeutic agents to alter oxidative balance in tumor cells may be selective for cancer cells and may ultimately have an impact on clinical efficacy and safety. Elucidating the translational potential of metabolic targeting could lead to the discovery of new approaches for treatment of metastatic cancer.

中文翻译：

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靶向线粒体代谢用于转移性癌症治疗

原发性肿瘤进化出有利于糖酵解以产生三磷酸腺苷（ATP）和抗氧化防御的代谢机制。相反，转移细胞常常依赖于线粒体呼吸和氧化磷酸化（OxPhos）。可以使用针对线粒体代谢的药物来利用转移细胞对 OxPhos 的依赖。因此，通过多种机制起作用的治疗剂，包括激活促进活性氧（ROS）产生的信号通路和/或减少抗氧化防御，可能会升高氧化应激并抑制肿瘤细胞存活。在这篇综述中，我们将提供 (1) 对通过增强 ROS 抑制癌细胞的功能选择性细胞外信号调节激酶 1/2 (ERK1/2) 抑制剂的机制分析，(2) 对线粒体作用的综述ATP合酶在氧化还原调节和耐药性中的作用，(3)抑制ERK信号传导和线粒体OxPhos以达到减少肿瘤转移和治疗耐药性的治疗目标的基本原理。我们实验室最近使用转移性黑色素瘤和乳腺癌模型的报告显示了针对 ERK1/2 信号传导和线粒体 ATP 合酶的新型且合理设计的治疗药物的临床前疗效，这些药物可调节 ROS 事件，从而预防或治疗转移性癌症。这些发现和其他发现表明，针对肿瘤的代谢需求和脆弱性可能会抑制转移途径和肿瘤生长。利用治疗剂改变肿瘤细胞氧化平衡的能力的方法可能对癌细胞具有选择性，并可能最终对临床疗效和安全性产生影响。阐明代谢靶向的转化潜力可能会导致发现治疗转移性癌症的新方法。