Hitting the bull’s-eye in metastatic cancers—NSAIDs elevate ROS in Mitochondria, inducing malignant cell death

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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.

Figures

  • Figure 1. PGC-1αmediated OxPhos activation and ROS generation promotes the metastatic cancer cell phenotype. Hypoxic non-metastatic cancer cells maintain a diminished level of mitochondrial metabolism. However, hypoxia causes PGC-1αand HIF-1α, HIF-2αoverexpression which induces in pro-metastatic cells the generation of a higher number of mitochondria, increased OxPhos flux for ATP synthesis and increased ROS levels, all leading to the epithelial-mesenchymal transition and formation of highly metastatic cells. Abbreviations: OxPhos, oxidative phosphorylation; ROS, reactive oxygen species; HIF-1, Hypoxia-Inducible Factor 1-alpha; PGC-1, Peroxisome Proliferatoractivated Receptor Gamma Co-activator 1-alpha.
  • Figure 2. Examples of non-steroidal anti-inflammatory drugs (NSAIDs) chemical structures.
  • Figure 3. NSAIDs as mitochondrially targeted drugs in metastatic cells. After NSAID treatment, a heightened pro-oxidative status is induced in the metastatic cells, but not in non-metastatic tumor cells. The events ensuing in the metastastic cells include decreasing levels of GSH, critical changes in the Cysteine-thiol/disulfide bond status of key proteins and increasing ROS production, which is followed by Ca2+ overload, collapse of Δψm, opening of the PTPC, release of cytochrome c and the other apoptosis-inducing factors leading to the death and elimination of these cells. Abbreviations: NSAIDS, non-steroidal anti-inflammatory drugs; GSH, reduced glutathione; ROS, reactive oxygen species, PTPC, mitochondrial permeability transition pore complex, MPT, mitochondrial membrane permeability transition.
  • Figure 4. NSAID target sites for Cysteine-Thiol (Cys-S) reactivity in metastatic cells. NSAIDs have a multitude of potential targets, many mitochondrial. First, the antioxidative defense systems in metastatic cancer cells are knocked out by inactivating Grx, Trx, GST, TrxR, increasing the GSSG/GSH, before other targets are affected. These include reaction with Cys-S(☆) protein targets such as Orai1 to block SOCE, Prx/p66shc complexes to release p66shc which then translocates into the mitochondrial intramembraneous space binding to cytochrome C to promote ROS, modification of Kv ATP channels and mitochondrial Calcium (Ca2+) uniporter (MCU) regulators to cause mCa2+ matrix influx, increasing ROS production and promoting mPTP complex formation (PTPC) leading to cell death. Abbreviations: MITO, mitochondria. ER, endoplasmic reticulum. SOCE, StoreOperated Calcium Entry. STIM, Stromal Interaction Molecules.

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CITATION STYLE

APA

Ralph, S. J., Pritchard, R., Rodríguez-Enríquez, S., Moreno-Sánchez, R., & Ralph, R. K. (2015, February 13). Hitting the bull’s-eye in metastatic cancers—NSAIDs elevate ROS in Mitochondria, inducing malignant cell death. Pharmaceuticals. MDPI AG. https://doi.org/10.3390/ph8010062

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