Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewDichloroacetate and cancer: New home for an orphan drug?
Introduction
A drug acting at a site integral to a cell's survival will exhibit a spectrum of dynamics determined by the physiological or pathological state of that cell. In the case of the xenobiotic dichloroacetate (DCA), its principal pharmacological target, the mitochondrial pyruvate dehydrogenase complex (PDC), is fundamental to eukaryotic life, so it is not surprising that acquired or congenital disorders of this mega-complex have profound ramifications for human health [1].
In this article, we focus on the anti-cancer properties of DCA, first described in the seminal report in 2007 by Bonnet and coworkers [2]. Since then, over 60 peer-reviewed laboratory and clinical investigations have contributed to establish DCA as a prototype of a new class of “metabolic modulators,” acting to revert a cancer cell's metabolism toward a more normal phenotype, a consequence that, ironically, initiates the malignant cell's demise. To place this interesting effect of DCA in proper context, it is fitting to summarize briefly how its study as a putative anti-cancer agent arose.
Section snippets
Getting here from there
DCA is a product of water chlorination and the metabolism of a few industrial solvents and drugs, fostering both its ubiquity throughout our biosphere and interest among a spectrum of disciplines, from environmental toxicology to medicine [3]. When administered orally as the sodium salt, DCA is rapidly absorbed, has a bioavailability approaching unity, transverses the plasma and mitochondrial membranes via the monocarboxylate and pyruvate transporter systems, respectively, readily crosses the
How it works
The multienzyme PDC is located in the mitochondrial matrix. The complex catalyzes the rate-limiting step in the aerobic oxidation of glucose, pyruvate, alanine and lactate to acetyl CoA and is thus integral to cellular energetics (Fig. 2) [22], [23], [24], [25]. Oxidative phosphorylation (OXPHOS) is initiated by the PDC or by the fatty acyl CoA dehydrogenase-catalyzed reactions. Regardless of the inherent integrity of the more distal tricarboxylic (TCA) cycle or respiratory chain, OXPHOS would
The PDC and cancer
Cancer cells derive much or most of their bioenergetic needs by means of glycolysis, rather than by mitochondrial oxidative metabolism, a cardinal feature of tumors first described by Otto Warburg over 80 years ago [61]. This phenomenon, known as the Warburg effect, occurs even in the presence of adequate oxygen supply (aerobic glycolysis) and leads to net lactate release by the tumor [62]. Over the last decade the Warburg effect has been reinterpreted in the light of modern biology and
DCA and cancer
DCA has been used alone or in combination with other treatments in tumors derived from all three germ layers at widely varying doses (Table 2) [2], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139],
Structural analogs
“Slow release” ionic complexes and esters containing DCA were synthesized originally to modify the plasma kinetics of the drug and prolong its dynamic action on intermediary metabolism [184]. Subsequently, other structural analogs were developed with the aim of increasing their molar potency toward PDK inhibition (Suppl. Table 2) [94], [112], [113], [117], [119], [122], [137], [142], [143], [144], [145], [147]. To date, there have been no published reports that these or any other analogs of DCA
Combination therapy
From the knowledge that aerobic glycolysis is associated with radiation and drug resistance by cancer cells [187], [188], a few studies have combined DCA with X-irradiation or standard chemotherapeutics in an effort to overcome resistance to these agents (Suppl. Table 2). Liao and coworkers [189] found that the radiation-induced senescence of MDA-MB-231-2A human breast cancer cells led to increased glycolysis and acidification of the tumor microenvironment, which were reversed by exposure to
Clinical use
Three early phase, open-label trials of oral DCA in cancer patients have been published, two in patients with brain tumors [13], [197] and one in patients with metastatic breast cancer or advanced non-small cell lung cancer [198]. In the first report, Michelakis et al. [197] administered 12.5 mg/kg twice daily to five adults, three with recurrent and two with newly diagnosed glioblastoma multiforme (GBM), one of whom was started on DCA alone and the other on standard treatment with radiation
Concluding remarks
Repurposing an old drug is often based on discovering new sites and mechanisms of action of the chemical. In the case of DCA, most of its dynamic effects are mediated by perturbation of the PDC/PDK axis and the resulting impact on carbohydrate metabolism and bioenergetics. Such is the basis for its reported beneficial actions in diabetes mellitus, acquired and congenital forms of lactic acidosis, myocardial and cerebral ischemia and, most recently, pulmonary arterial hypertension (PAH) and
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