Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer

By E. Michelakis, Linda Webster, John R. Mackey. British Journal of Cancer, 2008

670 citations recorded by the source corpus.

The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7567c81e1679dc0894ddba8c9035842e32dd4b02

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Citations in the corpus

Regulation of pyruvate metabolism and human disease (2013, background): “Studies in multiple cancer types, such as nonsmall cell lung carcinomas [166], squamous cell carcinomas [165], and breast carcinomas [167], have shown that upon dichloroacetate treatment cancer cell proliferation and tumor size decrease [168].”
Catabolic efficiency of aerobic glycolysis: The Warburg effect revisited (2010, background): “Pharmacological reduction of lactate production and excretion may indeed reduce the invasive potential of tumor cells or makes them more susceptible to apoptosis [25].”
Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. (2010, positive): “Importantly, inhibition of PDH kinases in KO cells by dichloroacetic acid (DCA, 2 mM) (Michelakis et al., 2008) reduced PDH phosphorylation (Figure 7C), restored OCR (Figure 7D), and reduced autophagy (Figure 7E) to control levels.”
Targeting cellular metabolism to improve cancer therapeutics (2013, background): “cells apoptosis resistance DCA serves as a potential metabolic-targeting molecule for sensitizing cancer cells to chemotherapy or radiotherapy.(76) DCA potentiates the antic-”
Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer (2016, background): “Decreased PDH flux has been described as a property of tumors, with PDH reactivation proposed as a cancer therapy (Michelakis et al., 2008).”