Hitting the Bull’s-Eye in Metastatic Cancers—NSAIDs Elevate ROS in Mitochondria, Inducing Malignant Cell Death

Abstract

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.

NSAID celecoxib: a potent mitochondrial pro-oxidant cytotoxic agent sensitizing metastatic cancers and cancer stem cells to chemotherapy

“…Hence, the pre-clinical findings are consistent with the ability of celecoxib to chemosensitize cancer cells rendering them more susceptible to other anticancer drugs. Drugs like celecoxib have proven to offer further advantages in that they have been shown to kill cancer cells independently of MDR [164,165] or p53 or DNA mismatch repair enzymes (reviewed in [152,166] ), because as we have shown, they kill by targeting mitochondrial metabolism [152][153][154]167] .…”

“…Previously, we reviewed the role of NSAIDs as "hitting the bulls-eye" in cancer cells by targeting mitochondrial function to trigger cell death via the intrinsic mitochondrial pathway of apoptosis [152] . Our more recent studies examined five different NSAIDs and showed that adding them to metastatic cancer cell lines in culture resulted in a progressive increase in ROS production from mitochondria to trigger ensuing cytotoxicity, by activating the intrinsic apoptotic signaling pathway.…”

Mitochondrial free fatty acid β-oxidation supports oxidative phosphorylation and proliferation in cancer cells

“…However, this view has been challenged by numerous recent studies demonstrating that in several metastatic cancers, OxPhos is the predominant ATP cellular supplier in strong preference over glycolysis (Moreno-Sánchez et al, 2007;Ralph et al, 2010;Zu and Guppy, 2004). Thus, active OxPhos and mitochondrial remodeling and ROS production have been associated with invasiveness onset (Zhao et al, 2013), metastatic and malignant phenotype acquisition Ralph et al, 2015), cellular cycle activation and autophagy resistance (Salem et al, 2012), and other mechanisms implicated in drug resistance (Indran et al, 2011;Lu and Chao, 2012).…”

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

“…Therefore, a more selective and specific targeting approach is needed that preferentially distinguishes cancer from normal cells. By changing the traditional approach of only looking for differences in the transcriptome or the proteome and instead searching for significant changes in function, such a target may be the reprogrammed redox metabolism found inside advanced stage cancer cells, particularly metastatic cells and cancer stem cells (CSCs; reviewed in Ralph et al and Skoda et al) (Table ).…”