Tumor metastases that impede the function of vital organs are a major cause of
cancer related mortality. Mitochondrial oxidative stress induced by
hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary
tumors to enhance their progression to
metastasis. Emerging evidence now indicates that mitochondrial modifications and mutations resulting from oxidative stress, and leading to OxPhos stimulation and/or enhanced
reactive oxygen species (ROS) production, are essential for promoting and sustaining the highly metastatic phenotype. Moreover, the modified mitochondria in emerging or existing metastatic
cancer cells, by their irreversible differences, provide opportunities for selectively targeting their mitochondrial functions with a one-two punch. The first blow would block their anti-oxidative defense, followed by the knockout blow-promoting production of excess ROS, capitulating the terminal stage-activation of the
mitochondrial permeability transition pore (mPTP), specifically killing metastatic
cancer cells or their precursors. This review links a wide area of research relevant to cellular mechanisms that affect mitochondria activity as a major source of ROS production driving the pro-oxidative state in metastatic
cancer cells. Each of the important aspects affecting mitochondrial function are discussed including:
hypoxia, HIFs and PGC1 induced metabolic changes, increased ROS production to induce a more pro-oxidative state with reduced
antioxidant defenses. It then focuses on how the mitochondria, as a major source of ROS in metastatic
cancer cells driving the pro-oxidative state of
malignancy enables targeting drugs affecting many of these altered processes and why the
NSAIDs are an excellent example of mitochondria-targeted agents that provide a one-two knockout activating the
mPTP and their efficacy as selective anticancer
metastasis drugs.