Metabolic reprogramming by Dichloroacetic acid potentiates photodynamic therapy of human breast adenocarcinoma MCF-7 cells

Abstract

Aberrant glycolytic metabolism is one of the hallmarks of carcinogenesis and therefore reversal of metabolic transformation is a promising drug target in cancer treatment strategies. Dichloroacetic acid (DCA) is known to target the glycolytic pathway in cancer cells and facilitates reversal of metabolic transformation from aerobic cytosolic accumulation of pyruvic acid, “the Warburg effect”, to mitochondrial oxidative phosphorylation. Recently, combination therapy particularly involving photodynamic therapy (PDT) has received considerable attention in oncology. We hypothesized that if DCA and PDT are combined, they might potentiate mitochondrial dysfunction and induce apoptosis by a reactive oxygen species (ROS) dependent pathway. We used MCF-7 cells as our in vitro model and 5-aminolevulinic acid (5-ALA) dependent PDT therapy to test our hypothesis. We found that combinatorial treatment of MCF-7 cells with PDT and DCA not only increased cell growth inhibition, but also affected mitochondrial membrane integrity perhaps via production of ROS, and enhanced apoptosis. Further, our results on ATP release during the combined treatment demonstrate that immunogenic cell death (ICD) is likely to be a potential mechanism by which PDT and DCA induce cancer cell death. Taken together, our study suggests a novel way of sensitizing MCF-7 cells for accelerated induction of apoptosis and ICD in these cells. The findings included in this study might have direct relevance in breast cancer treatment strategies.

In order for the light to shine so brightly, the darkness must be present—why do cancers fluoresce with 5-aminolaevulinic acid?

“…Combining 5-ALA PDT with dichloroacetate significantly reduced cell viability in breast cancer (MCF7) cells (PpIX levels were not measured in this study). 57 Dichloroacetate alters the flux of pyruvate in the mitochondria thereby diverting glucose metabolism from glycolysis to oxidation. 58 These in vitro studies all suggest targeting glucose metabolism has the potential to enhance 5-ALA therapy, although further exploration is needed on the mechanistic links between altered glucose metabolism and haem synthesis in the cancer cell.…”

Dichloroacetate and PX-478 Exhibit Strong Synergistic Effects in a Various Number of Cancer Cell Lines.

“…In addition to its effects on the mitochondrial membrane potential, DCA is believed to lead to a signi cant increase in reactive oxygen species (ROS) generation, which plays an important role in the induction of apoptosis (10)(11)(12)(13)(14). By contrast, other authors reported that DCA may function as a sensitizer for ROS induced alterations, but did not signi cantly increase ROS production per se (13,15). The DCA dose as well as the metabolic state of the cell may impact DCA-mediated ROS production.…”

Mitochondrial Flexibility of Breast Cancers: A Growth Advantage and a Therapeutic Opportunity

“…PDT, using visible or near-infrared light with a photosensitiser, generates high levels of ROS, which efficiently affect both cancer cells and tumour microenvironment. In fact, PDT can exert direct cytotoxic effects on tumour cells, and reprogram the tumour microenvironment to exert a potent anti-tumour immune response [139]. Nawab Ali group showed that combined treatment of MCF-7 breast cancer cells with PDT and DCA inhibits cell growth, decreases mitochondrial membrane integrity, probably through ROS production, and enhances apoptosis [139].…”

“…In fact, PDT can exert direct cytotoxic effects on tumour cells, and reprogram the tumour microenvironment to exert a potent anti-tumour immune response [139]. Nawab Ali group showed that combined treatment of MCF-7 breast cancer cells with PDT and DCA inhibits cell growth, decreases mitochondrial membrane integrity, probably through ROS production, and enhances apoptosis [139]. Moreover, ICD could be considered as a potential cancer cell death mechanism induced by the anti-tumour combinatorial treatment with PDT and DCA.…”

“…This study, showing the possibility of sensitising MCF-7 cells to both apoptosis and ICD, offers an additional therapeutic approach in ER + breast cancer treatment. This novel therapeutic approach could overcome the non-immunogenic properties, metabolic transformation, and therapy resistance of cancer cells [139].…”