Combination of 2-deoxy d-glucose and metformin for synergistic inhibition of non-small cell lung cancer: A reactive oxygen species and P-p38 mediated mechanism.
Targeting metabolism of lung cancer cells is a promising methodology for the treatment of lung cancer. In this regard, 2-Deoxy d-glucose (2-dDG) has been reported to inhibit cell proliferation by intervening the glycolytic pathway. However, phase I clinical trial of 2-dDG demonstrated cardiac side effects at higher dosage. Metformin (Met), on the other hand, has been reported to improve pathological response to chemotherapy in non-small cell lung cancer (NSCLC) patients. In this study, we propose that combination therapy of 2-dDG with Met will demonstrate enhanced cytotoxicity than either compound alone. Our results indicated that inhibition concentration 25 (IC25) for combined treatment of Met and 2-dDG showed more toxicity as compared to individual agents on a NSCLC cell line, A549. This augmented toxicity is associated with increased lipid peroxidation and decreased glutathione level as well as decreased super oxide dismutase and catalase activities. Combination of Met and 2-dDG also demonstrated enhanced DNA damage, DNA adduct formation, intracellular reactive oxygen species (ROS) level, and mitochondrial membrane potential alteration, as well as increased apoptosis, caspase-3 activity, P-p38 and P-AMP-activated protein kinase (AMPK) level. It was also shown that inhibition of caspase-3 and p38 kinase partially (75%-87%) reversed Met and 2-dDG induced cell death, without affecting the ROS levels. On the other hand, pre-treatment of cells with N-acetyl cysteine (NAC) reversed Met and 2-dDG induced cell death to >90%. Taken together, the results of this study demonstrated that combination of Met and 2-dDG showed better toxicity than individual compounds and cell death is ROS, P-p38 and caspase-3 mediated, thereby providing a proof of concept for the combination of Met and 2-dDG as a potential treatment protocol for NSCLC.
Department of Thoracic Surgery, PLA General hospital, Beijing100853, China.
Xiao-Bin
XB
Hou
Department of Dermatology, PLA 309 Hospital, Beijing 100091, China.
Ting-Hui
TH
Li
Department of Thoracic Surgery, PLA General hospital, Beijing100853, China.
Zhi-Peng
ZP
Ren
Department of Thoracic Surgery, PLA General hospital, Beijing100853, China. Electronic address: Liu_yang@126.com.
Yang
Y
Liu
D000072283:A549 Cells; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D003847:Deoxyglucose / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000975:Antioxidants; D018736:DNA Adducts; D017382:Reactive Oxygen Species; D008687:Metformin; D003847:Deoxyglucose; D007770:L-Lactate Dehydrogenase; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3
2-deoxyd-glucoce; Apoptosis; Combination therapy; Lung cancer; Metformin