Review
Dichloroacetate and cancer: New home for an orphan drug?

https://doi.org/10.1016/j.bbcan.2014.08.005Get rights and content

Highlights

  • We review studies from 2007 through May, 2014 on the anti-tumor effects of DCA.

  • DCA's effects are based mainly on reversing the Warburg effect in tumors.

  • It inhibits pyruvate dehydrogenase (PD) kinase, thereby activating the PD complex.

  • DCA, and its analogs, synergize with many standard anti-cancer agents.

  • Early phase clinical trials suggest chronic DCA is safe and well-tolerated.

Abstract

We reviewed the anti-cancer effects of DCA, an orphan drug long used as an investigational treatment for various acquired and congenital disorders of mitochondrial intermediary metabolism. Inhibition by DCA of mitochondrial pyruvate dehydrogenase kinases and subsequent reactivation of the pyruvate dehydrogenase complex and oxidative phosphorylation is the common mechanism accounting for the drug's anti-neoplastic effects. At least two fundamental changes in tumor metabolism are induced by DCA that antagonize tumor growth, metastases and survival: the first is the redirection of glucose metabolism from glycolysis to oxidation (reversal of the Warburg effect), leading to inhibition of proliferation and induction of caspase-mediated apoptosis. These effects have been replicated in both human cancer cell lines and in tumor implants of diverse germ line origin. The second fundamental change is the oxidative removal of lactate, via pyruvate, and the co-incident buffering of hydrogen ions by dehydrogenases located in the mitochondrial matrix. Preclinical studies demonstrate that DCA has additive or synergistic effects when used in combination with standard agents designed to modify tumor oxidative stress, vascular remodeling, DNA integrity or immunity. These findings and limited clinical results suggest that potentially fruitful areas for additional clinical trials include 1) adult and pediatric high grade astrocytomas; 2) BRAF-mutant cancers, such as melanoma, perhaps combined with other pro-oxidants; 3) tumors in which resistance to standard platinum-class drugs alone may be overcome with combination therapy; and 4) tumors of endodermal origin, in which extensive experimental research has demonstrated significant anti-proliferative, pro-apoptotic effects of DCA, leading to improved host survival.

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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