2-Deoxyglucose pretreatment sensitizes colon cancer cells to cisplatin and killer trail induced apoptosis by Mcl-1 downregulation

Official URL: http://192.168.1.20/record=b1378201 (Table of Contents)

Altered metabolism of cancer cells provides new therapeutic strategies for anticancer treatment. Cancer cells preferentially select glycolysis and lactic acid fermentation for their metabolic requirements, even in the presence of sufficient oxygen. Targeting cancer cell metabolism gave promising results as the treatments are offering therapeutic selectivity in the name of killing cancer cells more effectively while sparing normal cells. Coupling glycolysis inhibition with chemotherapy is one of the new strategies against cancer. In this thesis, we have studied with colon cancer cell lines HCT 116 WT, p53-/- and Bax-/-. Glycolysis inhibition was achieved with a glucose analog, 2-Deoxyglucose (2-DG) which is at the stage of clinical trials. Cisplatin and TNF-related apoptosis-inducing ligand (Killer TRAIL) were selected as anticancer agents. Pretreatment of 2-DG prior to cisplatin and Killer TRAIL treatment sensitized the cells to apoptotic cell death induced by these anticancer agents and increased cell death numbers. We observed several mechanisms to this sensitization effect. 2-DG sensitizes the cells to cisplatin and Killer TRAIL-induced apoptosis via downregulation of a crucial antiapoptotic protein Mcl-1, belonging to the Bcl-2 protein family. ATP depletion due to inhibition of glycolysis and cell cycle arrest are other contributing mechanisms. 2-DG also caused activation of energy biosensor AMPK and inhibition of cell growth and protein synthesis regulator mTOR. For a detailed analysis of 2-DG's effects on the gene level, RNA microarray study was conducted. The results of this study harmonized with the data indicated.