Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A re-sensitizes Taxol-resistant cancer cells to Taxol

Ming Zhou,Adam I Riker,Sushama Kamarajugadda,Yan Ding,Zixing Liu,Laurie B Owen,Yuhua Zhao,Oystein Fodstad,Susan P Ledoux,Jianrong Lu,Hao Liu,Ming Tan

doi:10.1186/1476-4598-9-33

Abstract

BackgroundTaxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Despite impressive clinical responses initially, the majority of patients eventually develop resistance to Taxol. Lactate dehydrogenase-A (LDH-A) is one of the predominant isoforms of LDH expressed in breast tissue, which controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism. In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells.ResultsTaxol-resistant subclones, derived from the cancer cell line MDA-MB-435, sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not. The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells. The downregulation of LDH-A by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol. A higher sensitivity to the specific LDH inhibitor, oxamate, was found in the Taxol-resistant cells. Furthermore, treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells.ConclusionLDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol. This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance. To our knowledge, this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells. This study provides valuable information for the future development and use of targeted therapies, such as oxamate, for the treatment of patients with Taxol-resistant breast cancer.

Highlights

Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer
Stage apoptosis was examined by flow cytometry analysis after staining with Annexin V/propidium iodide, and late stage apoptosis was detected by a Cell Death Detection ELISA PLUS kit, which examines the DNA fragmentation in the apoptotic cells
The protein expression of the cleaved Poly (ADP-ribose) polymerase (c-PARP), an important marker of caspasemediated apoptosis [19,20], was examined by Western blotting after the cells were treated with 20 nM Taxol for 48 hrs

Summary

Introduction

Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Taxol (paclitaxel) has recently emerged as an important agent in the treatment of human breast cancer as well as other tumor histologies, such as ovarian, prostate and non-small cell lung cancers [1,2]. Taxol stabilizes the microtubule structure by disrupting the dynamic equilibrium between soluble tubulin dimers and their polymerized form. It is a potent inhibitor of chromosomal replication by blocking cells in the late G2 or mitotic phases of the cell cycle [3]. One known mechanism involved with cancer cell resistance to Taxol and other microtubule-stabilizing agents is the high-expression of the membrane P-glycoprotein that functions as a drugefflux pump [6]. The detailed molecular mechanisms that may contribute to Taxol resistance of cancer cells are still not fully understood

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