Abstract
Reverting glycolytic metabolism is an attractive strategy for cancer therapy as upregulated glycolysis is a hallmark in various cancers. Dichloroacetate (DCA), long used to treat lactic acidosis in various pathologies, has emerged as a promising anti-cancer drug. By inhibiting the pyruvate dehydrogenase kinase, DCA reactivates the mitochondrial function and decreases the glycolytic flux in tumor cells resulting in cell cycle arrest and apoptosis. We recently documented that DCA was able to induce a metabolic switch preferentially in glycolytic cancer cells, leading to a more oxidative phenotype and decreasing proliferation, while oxidative cells remained less sensitive to DCA treatment. To evaluate the relevance of this observation in vivo, the aim of the present study was to characterize the effect of DCA in glycolytic MDA-MB-231 tumors and in oxidative SiHa tumors using advanced pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by 17O magnetic resonance spectroscopy, glucose uptake, evaluated by 18F-FDG PET and pyruvate transformation into lactate, measured using hyperpolarized 13C-magnetic resonance spectroscopy, were monitored before and 24 hours after DCA treatment in tumor bearing mice. In both tumor models, no clear metabolic shift was observed. Surprisingly, all these imaging parameters concur to the conclusion that both glycolytic tumors and oxidative tumors presented a similar response to DCA. These results highlight a major discordance in metabolic cancer cell bioenergetics between in vitro and in vivo setups, indicating critical role of the local microenvironment in tumor metabolic behaviors.
Highlights
Warburg metabolism is a common feature of several malignant tumors and is associated with cancer aggressiveness, invasiveness and poor prognosis [1,2,3]
We found that DCA treatment did not lead to a significant change in the uptake of 18F-FDG (Figure 2A-2D), assessing a limited impact of DCA on glucose uptake (Figure 2E). %ID/g measured on PET images were 1.88 ± 0.12 under baseline condition and 1.78 ± 0.11 after treatment for MDA-MB-231 tumors (n=7, P=0.2120) and 1.79 ± 0.21 under baseline condition and 1.89 ± 0.19 after treatment for SiHa tumors (n=7, P=0.0813)
We previously identified clear effects of DCA treatment on oxygen consumption, glucose consumption and lactate uptake in glycolytic MDAMB-231 human breast cancer cells
Summary
Warburg metabolism (enhanced glycolysis in the presence of oxygen) is a common feature of several malignant tumors and is associated with cancer aggressiveness, invasiveness and poor prognosis [1,2,3]. Because of this high glycolytic rate in various cancers, targeting glucose metabolism is presented as an attractive anticancer approach endowed with a high specificity and limited undesirable side effects [4, 5]. Treatments targeting glycolytic metabolism should instead alter metabolic adaptations that support the Warburg malignant phenotype, adaptations that are not shared by normal cells. For new cytostatic agents targeting tumor metabolism, the use of conventional anatomical imaging techniques is not optimal for treatment response assessment [4] and only functional and molecular imaging techniques may offer the possibility of an early assessment of the tumor response [6,7,8]
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