Abstract
Ethyl pyruvate, a known ROS scavenger and anti-inflammatory drug was found to combat leukemia cells. Tumor cell killing was achieved by concerted action of necrosis/apoptosis induction, ATP depletion, and inhibition of glycolytic and para-glycolytic enzymes. Ethyl lactate was less harmful to leukemia cells but was found to arrest cell cycle in the G0/G1 phase. Both, ethyl pyruvate and ethyl lactate were identified as new inhibitors of GSK-3β. Despite the strong effect of ethyl pyruvate on leukemia cells, human cognate blood cells were only marginally affected. The data were compiled by immune blotting, flow cytometry, enzyme activity assay and gene array analysis. Our results inform new mechanisms of ethyl pyruvate-induced cell death, offering thereby a new treatment regime with a high therapeutic window for leukemic tumors.
Highlights
Leukemia is one of the main causes of death in cancer patients
Chemotherapy is most frequently used in leukemia treatment, it has been associated with many side effects such as systemic cytotoxicity and multi-drug resistance [1,2,3].To overcome such problems, various anti-cancer drugs have been applied in combination or given together with substances that increase sensitivity of leukemia cells to chemotherapy such as butyrate [4]
RPMI-1640 medium, fetal calf serum (FCS) and trypan blue were purchased from Seromed (Berlin); anti-human GLO1 monoclonal antibody was from BioMac (Leipzig, Germany); cell proliferation WST-1 reagent from Roche; anti-human β-actin mAb was from Abgent (Hamburg); HRP-labeled goat anti-mouse Ab and Real Detection System Peroxidase/ 3,3'-diaminobenzidine (DAB) Rabbit/Mouse Kit from Dako (Hamburg); anti-human GAPDH, anti-human phospho(Ser9)-glycogensynthasekinase-3β (anti-phospho GSK3β (Ser9), anti-human GSK-3β, pan-phospho-β-catenin (Ser33/37/ Thr41) antibodies from Cell Signaling; protease inhibitor cocktail, RNAse, Ethyl pyruvate (EP), ELannexin-V-fluoresceine isothiocyanate (FITC), propidium iodine (PI) and lactate dehydrogenase (LDH)-1 were obtained from SigmaAldrich (Taufkirchen); chemiluminescence detection kit from Boehringer (Mannheim); RT2 ProfilerTM PCR Array: Human WNT Signalling Pathway(Cat
Summary
Leukemia is one of the main causes of death in cancer patients. chemotherapy is most frequently used in leukemia treatment, it has been associated with many side effects such as systemic cytotoxicity and multi-drug resistance [1,2,3].To overcome such problems, various anti-cancer drugs have been applied in combination or given together with substances that increase sensitivity of leukemia cells to chemotherapy such as butyrate [4].Ethyl pyruvate (EP) has attracted increasing interest in new treatment modalities of different diseases such as malignancies, inflammation and reperfusion syndrome [5,6,7,8]. Leukemia is one of the main causes of death in cancer patients. Chemotherapy is most frequently used in leukemia treatment, it has been associated with many side effects such as systemic cytotoxicity and multi-drug resistance [1,2,3].To overcome such problems, various anti-cancer drugs have been applied in combination or given together with substances that increase sensitivity of leukemia cells to chemotherapy such as butyrate [4]. Ethyl pyruvate (EP) has attracted increasing interest in new treatment modalities of different diseases such as malignancies, inflammation and reperfusion syndrome [5,6,7,8]. The mechanism of action is still unsolved and a number of different targets are reckoned. Based on earlier work of Fink et al [9] EP substituted pyruvate as a ROS scavenger and antioxidant in clinical
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