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Simple Summary: Breast cancer cells exhibit a high degree of metabolic plasticity, allowing them to shift between glycolytic and mitochondrial ATP-producing pathways as a means of adapting to and surviving in a variety of growth conditions. Consequently, breast cancer cells exposed to a single chemotherapeutic agent that inhibits only one of these major cellular ATP-producing pathways can meet their energy demands by using the alternative pathway. This study explored a novel drug combination aimed simultaneously at both means of energy production in MCF7 and MDA-MB-231 breast adenocarcinoma cells. Our data show that dual treatment of these cells with the mitochondria-targeting anticancer agent, elesclomol, and either glycolytic inhibitor, 2-deoxy-D-glucose or 3-bromopyruvate resulted in greater cytotoxic and antiproliferative effects than those induced by any of the compounds used as a single agent. These results suggest the possibility of a novel and effective combination treatment for the enhanced cytotoxicity of breast cancer cells. Background/Objectives: Glycolysis and mitochondrial oxidative phosphorylation are the two major metabolic pathways for cellular ATP production. The metabolic plasticity displayed by cancer cells allows them to effectively shift between each of these pathways as a means of adapting to various growth conditions, thus ensuring their survival, proliferation and disease progression. Metabolic plasticity also provides cancer cells with the ability to circumvent many traditional monotherapies aimed at only one or the other of the major ATP-producing pathways. The purpose of this study was to determine the effectiveness of a dual treatment strategy aimed simultaneously at both pathways of ATP production in human breast cancer cells. It was hypothesized that concurrent exposure of these cells to the mitochondria-targeting chemotherapeutic agent, elesclomol, in combination with either of two glycolytic inhibitors, 2-deoxy-D-glucose or 3-bromopyruvate, would yield greater in vitro anticancer effects than those observed for any of the compounds used as a single agent. Methods: Cytotoxicity and clonogenic assays were employed to assess the survival and proliferation of MCF7 and MDA-MB-231 human breast adenocarcinoma cells exposed to the compounds alone and in combination. Results: The data obtained show that the cancer-cell-killing and antiproliferative effects of the dual treatment were significantly enhanced compared to those observed for any of the compounds alone. Conclusions: The results of this study are important in that they suggest the possibility of a novel and effective chemotherapeutic strategy for breast cancer cell killing. [ABSTRACT FROM AUTHOR]

Abstract: Gliomas are characterized by a marked glycolytic metabolism with a consequent production of massive amounts of lactate, even in the presence of normal levels of oxygen, associated to increased invasion capacity and to higher resistance to conventional treatment. This work aimed to understand how the metabolic modulation can influence tumour aggressive features and its potential to be used as complementary therapy. We assessed the effect of bioenergetic modulators (BMs) targeting different metabolic pathways in glioma cell characteristics. The in vivo effect of BMs was evaluated using the chicken chorioallantoic membrane model. Additionally, the effect of pre‐treatment with BMs in the response to the antitumour drug temozolomide (TMZ) was analysed in vitro. Cell treatment with the BMs induced a decrease in cell viability and in migratory/invasion abilities, as well as modifications in metabolic parameters (glucose, lactate and ATP) and increased the cytotoxicity of the conventional drug TMZ. Furthermore, all BMs decreased the tumour growth and the number of blood vessels in an in vivo model. Our results demonstrate that metabolic modulation has the potential to be used as therapy to decrease the aggressiveness of the tumours or to be combined with conventional drugs used in glioma treatment. [ABSTRACT FROM AUTHOR]

Abstract: Cancer cells are characterized by self-sufficiency in the absence of growth signals, their ability to evade apoptosis, resistance to anti-growth signals, sustained angiogenesis, uncontrolled proliferation, and invasion and metastasis. Alterations in cellular bioenergetics are an emerging hallmark of cancer. The mitochondrion is the major organelle implicated in the cellular bioenergetic and biosynthetic changes accompanying cancer. These bioenergetic modifications contribute to the invasive, metastatic and adaptive properties typical in most tumors. Moreover, mitochondrial DNA mutations complement the bioenergetic changes in cancer. Several cancer management therapies have been proposed that target tumor cell metabolism and mitochondria. Glycolytic inhibitors serve as a classical example of cancer metabolism targeting agents. Several TCA cycle and OXPHOS inhibitors are being tested for their anticancer potential. Moreover, agents targeting the PDC/PDK (pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase) interaction are being studied for reversal of Warburg effect. Targeting of the apoptotic regulatory machinery of mitochondria is another potential anticancer field in need of exploration. Additionally, oxidative phosphorylation uncouplers, potassium channel modulators, and mitochondrial redox are under investigation for their anticancer potential. To this end there is an increased demand for agents that specifically hit their target. Delocalized lipophilic cations have shown tremendous potential in delivering anticancer agents selectively to tumor cells. This review provides an overview of the potential anticancer agents that act by targeting cancer cell metabolism and mitochondria, and also brings us face to face with the emerging opportunities in cancer therapy. [Copyright &y& Elsevier]