Preventing cancer metastasis with specific inhibitors of mitochondrial superoxide

Metabolism is a key driver of cancer progression and resistance to treatments. In this study, we further considered that mitochondria within cancer cells could act as metabolic sensors, triggering cancer cell migration, invasion and metastasis. This hypothesis considers that metabolically hostile mircroenvironments could trigger mitochondrial dysfunctions and cell escape from primary tumors. In vitro and in vivo rounds of selection for invasion and metastasis yielded superinvasive and supermetastatic cancer cells that were metabolically compared to the isogenic weakly invasive and weakly metastatic that served as initial material. We report that metastatic progenitor cells produce mitochondrial superoxide, the inhibition of which prevents metastasis. Conversely, weakly metastatic cancer cells manipulated to produce more mitochondrial superoxide gain a metastatic phenotype. Consequently, targeting mitochondrial superoxide with superoxide scavengers such as mitoTEMPO and mitoQ strongly and sometimes fully inhibited the metastatic burden of breast and melanoma cancer models in mice

Molecular signature for assessing the responsiveness of cancer to mitochondria-targeted antioxidants

The present invention relates to the field of personalized 5 medicine, and in particular to molecular signatures allowing the identification of individuals with cancer as being susceptible to respond to a treatmen

Metabolic and non-metabolic pathways that control cancer resistance to anthracyclines.

Anthracyclines Doxorubicin, Epirubicin, Daunorubicin and Idarubicin are used to treat a variety of tumor types in the clinics, either alone or, most often, in combination therapies. While their cardiotoxicity is well known, the emergence of chemoresistance is also a major issue accounting for treatment discontinuation. Resistance to anthracyclines is associated to the acquisition of multidrug resistance conferred by overexpression of permeability glycoprotein-1 or other efflux pumps, by altered DNA repair, changes in topoisomerase II activity, cancer stemness and metabolic adaptations. This review further details the metabolic aspects of resistance to anthracyclines, emphasizing the contributions of glycolysis, the pentose phosphate pathway and nucleotide biosynthesis, glutathione, lipid metabolism and autophagy to the chemoresistant phenotype

An EPR study using cyclic hydroxylamines to assess the level of mitochondrial ROS in superinvasive cancer cells

It has been proposed that a mitochondrial switch involving a high mitochondrial superoxide production is associated with cancer metastasis. We here report an EPR analysis of ROS production using cyclic hydroxylamines in superinvasive SiHa-F3 compared with less invasive SiHa wild-type human cervix cancer cells. Using the CMH probe, no significant difference was observed in the overall level of ROS between SiHa and SiHa-F3 cells. However, using mitochondria-targeted cyclic hydroxylamine probe mitoTEMPO-H, we detected a significantly higher mitochondrial ROS content in SiHa-F3 compared with the wild-type SiHa cells. To investigate the nature of mitochondrial ROS, we overexpressed superoxide dismutase 2, a SOD isoform exclusively localized in mitochondria, in SiHa-F3 superinvasive cells. A significantly lower signal was detected in SiHa-F3 cells overexpressing SOD2 compared with SiHa-F3. Despite some limitations discussed in the paper, our EPR results suggest that mitochondrial ROS (at least partly superoxide) are produced to a larger extent in superinvasive cancer cells compared with less invasive wild-type cancer cells

Role of methamphetamine on glioblastoma cytotoxicity induced by doxorubicin and methotrexate.

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor with a high mortality rate. Doxorubicin (DOX) and methotrexate (MTX) showed to be effective against a wide range of tumors, but its use in GBM treatment is limited in part due to the inability to cross the blood-brain barrier (BBB). Based on recent studies demonstrating that methamphetamine (METH) increases BBB permeability, we hypothesized that it could be used as a pharmacological tool to allow the entry of potential therapeutic drugs into the brain. Nevertheless, before attempting this approach it is crucial to understand the cytotoxicity of such drug combinations. Herein, we evaluated the effects of METH on cell viability, migration, chemotaxis, and cell cycle, as well as its modulator effects on DOX or MTX-induced cytotoxicity in a human U118 GBM cell line. Our results demonstrated that both chemotherapeutic drugs DOX and MTX induced a pronounced decrease in cell viability, migration, and chemotaxis, and led to a cell cycle arrest at G2 and S phases, respectively. Additionally, METH (1 μM) neither interfered with U-118 cell viability, migration, or cell cycle nor modified DOX- or MTX-induced cytotoxicity. Noteworthy, METH by itself impaired cell chemotaxis with a similar effect to that induced by DOX or MTX alone. Overall, we can conclude that both DOX and MTX are highly cytotoxic against GBM cells and that METH, at a concentration previously shown to increase endothelial cell permeability without leading to cell death, does not interfere with the cytotoxicity of both chemotherapeutic drugs

Mitochondria in cancer

The rediscovery and reinterpretation of the Warburg effect from year 2000 occulted for almost a decade the key functions exerted by mitochondria in cancer cells. Until recent times, the scientific community indeed focused on constitutive glycolysis as a hallmark of cancer cells, which it is not, largely ignoring the contribution of mitochondria to the malignancy of oxidative and glycolytic cancer cells, being Warburgian or merely adapted to hypoxia. In this review, we highlight that mitochondria are not only powerhouses in some cancer cells, but also dynamic regulators of life, death, proliferation, motion and stemness in other types of cancer cells. Similar to the cells that host them, mitochondria are capable to adapt to tumoral conditions, and probably to evolve to ‘oncogenic mitochondria’ capable of transferring malignant capacities to recipient cells. In the wider quest of metabolic modulators of cancer, treatments have already been identified targeting mitochondria in cancer cells, but the field is still in infancy