Targeting Cellular Metabolism Chemosensitizes the Doxorubicin-Resistant Human Breast Adenocarcinoma Cells.

Shulan Ma,Rongfei Jia,Bo Shen,Dongju Li

doi:10.1155/2015/453986

Shulan Ma, Rongfei Jia + Show 2 more

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https://doi.org/10.1155/2015/453986

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Abstract

Metabolic energy preferentially produced by glycolysis was an advantageous metabolic phenotype of cancer cells. It is also an essential contributor to the progression of multidrug resistance in cancer cells. By developing human breast cancer MCF-7 cells resistant to doxorubicin (DOX) (MCF-7/MDR cells), the effects and mechanisms of 2-deoxy-D-glucose (2DG), a glucose analogue, on reversing multidrug resistance were investigated. 2DG significantly inhibited the viability of MCF-7/MDR cells and enhanced DOX-induced apoptosis by upregulating protein expression of AMPKα, P53, and caspase-3. The study demonstrated that energy restriction induced by 2DG was relevant to the synergistic effect of 2DG and DOX. The proteins of multidrug gene (the MDR-related protein, MRP1) and P-glycoprotein (P-gp) in MCF-7/MDR cells were downregulated after exposure to 2DG, accompanied with the suppression of the activity of ATP-dependent drug-efflux pump and transmembrane transporter, increasing the intracellular accumulation of DOX to reverse the chemoresistance in multidrug cancer cells.

Highlights

Scientific literature indicates that cancer cells predominantly generate energy by a high rate of glycolysis rather than the Krebs cycle of mitochondrial metabolism even when oxygen is abundant, which is called Warburg’s effect [1]
The development of MDR is accompanied with the overexpression of ATP-dependent drug-efflux pump, such as p-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and the breast cancer resistance protein (BCRP), which is thought to be an essential obstacle to reducing intracellular drug accumulation in tumor eradication [5]
The resistance of MCF-7/MDR cell line towards DOX was testified with Cell Counting Kit-8 (CCK8) assay

Summary

Introduction

Scientific literature indicates that cancer cells predominantly generate energy by a high rate of glycolysis rather than the Krebs cycle of mitochondrial metabolism even when oxygen is abundant, which is called Warburg’s effect [1]. The development of multidrug resistance (MDR) is an unfavorable factor in the poor prognosis for breast cancer. The development of MDR is accompanied with the overexpression of ATP-dependent drug-efflux pump, such as p-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and the breast cancer resistance protein (BCRP), which is thought to be an essential obstacle to reducing intracellular drug accumulation in tumor eradication [5]. We developed DOX-resistant MCF7 cells and examined the antiproliferative effect of DOX when the cellular metabolism was modulated with a glucose inhibitor. The results showed that energy restriction sensitized the DOX-resistant MCF-7 cells and enhanced the apoptosis induced by DOX. BioMed Research International induced a dramatic reduction in cellular ATP levels, the possible mechanism may be related to the functions of drug-efflux pumps, where the activity of transmembrane transporters regulates the energy restriction

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