Dichloroacetate restores drug sensitivity in paclitaxel-resistant cells by inducing citric acid accumulation.

Xiang Zhou,Ruohua Chen,Gang Huang,Jiajin Li,Zhenhai Yu,Rui Li,Jianjun Liu,Xiaoping Zhao,Shaoli Song

doi:10.1186/s12943-015-0331-3

Xiang Zhou, Ruohua Chen + Show 7 more

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https://doi.org/10.1186/s12943-015-0331-3

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Abstract

BackgroundThe Warburg effect describes the increased reliance of tumor cells on glycolysis for ATP generation. Mitochondrial respiratory defect is thought to be an important factor leading to the Warburg effect in some types of tumor cells. Consequently, there is growing interest in developing anti-cancer drugs that target mitochondria. One example is dichloroacetate (DCA) that stimulates mitochondria through inhibition of pyruvate dehydrogenase kinase.MethodsWe investigated the anti-cancer activity of DCA using biochemical and isotopic tracing methods.ResultsWe observed that paclitaxel-resistant cells contained decreased levels of citric acid and sustained mitochondrial respiratory defect. DCA specifically acted on cells with mitochondrial respiratory defect to reverse paclitaxel resistance. DCA could not effectively activate oxidative respiration in drug-resistant cells, but induced higher levels of citrate accumulation, which led to inhibition of glycolysis and inactivation of P-glycoprotein.ConclusionsThe abilityof DCA to target cells with mitochondrial respiratory defect and restore paclitaxel sensitivity by inducing citrate accumulation supports further preclinical development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0331-3) contains supplementary material, which is available to authorized users.

Highlights

The Warburg effect describes the increased reliance of tumor cells on glycolysis for ATP generation
Mouse monoclonal anti-P-glycoprotein was purchased from Santa Cruz Biotechnology and rabbit polyclonal antiPDK2 was purchased from Protein Tech. 99mTc-MIBI was purchased from Shanghai Hinko and 18 F-fluorodeoxyglucose was produced in our laboratory
Paclitaxel increases production of reactive oxygen species (ROS) in tumor cells that may result in mitochondrial injury because of long-term ROS-induced oxidative stress and a compromised mtRNA self-repair mechanism [35]

Summary

Introduction

The Warburg effect describes the increased reliance of tumor cells on glycolysis for ATP generation. One example is dichloroacetate (DCA) that stimulates mitochondria through inhibition of pyruvate dehydrogenase kinase. Positron emission tomography (PET) has since confirmed that most tumors undergo increased glucose uptake and metabolism [2]. This phenomenon is known as the Warburg effect, which is believed to reflect mitochondrial injury and alternative isoforms of glycolytic enzymes in cancer cells [3,4]. Mitochondrial respiratory injury is due primarily to mutations in mitochondrial DNA, reduced activity of key Dichloroacetate (DCA) activates pyruvate dehydrogenase complex (PDC) by inhibiting pyruvate dehydrogenase kinase (PDK). Activation of PDC converts pyruvate into acetyl-CoA, which is converted into citric acid in the mitochondria, stimulating mitochondrial oxidative phosphorylation [9]

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