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Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

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

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

Published in: Molecular Cancer | Issue 1/2015

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Abstract

Background

The 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.

Methods

We investigated the anti-cancer activity of DCA using biochemical and isotopic tracing methods.

Results

We 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.

Conclusions

The abilityof DCA to target cells with mitochondrial respiratory defect and restore paclitaxel sensitivity by inducing citrate accumulation supports further preclinical development.
Appendix
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Metadata
Title
Dichloroacetate restores drug sensitivity in paclitaxel-resistant cells by inducing citric acid accumulation
Authors
Xiang Zhou
Ruohua Chen
Zhenhai Yu
Rui Li
Jiajin Li
Xiaoping Zhao
Shaoli Song
Jianjun Liu
Gang Huang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0331-3

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