Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells

• Published in: PloS one Vol. 8; no. 6; p. e67081
• Main Authors: Vuyyuri, Saleha B, Rinkinen, Jacob, Worden, Erin, Shim, Hyekyung, Lee, Sukchan, Davis, Keith R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.06.2013; Public Library of Science (PLoS)
• Subjects: Acids; Adenosine diphosphate; Annexin V; Anticancer properties; Antineoplastic Agents - pharmacology; Antioxidants; Antitumor activity; Apoptosis; Apoptosis - drug effects; Ascorbic acid; Ascorbic Acid - pharmacology; Autophagy; B cells; Biology; Biotechnology; Cancer; Cancer therapies; Cancer treatment; Carcinoma, Non-Small-Cell Lung - metabolism; Caspase; Catalase; Cell cycle; Cell death; Cell growth; Cell Line, Tumor; Cell Survival - drug effects; Comparative analysis; Cytotoxicity; Dehydrogenases; Deoxyribonucleic acid; DNA; DNA fragmentation; Drug dosages; Drug Synergism; Enzymes; Epithelial cells; Gangrene; Gene expression; Glucose metabolism; Glycolysis; Glycolysis - drug effects; Humans; Inhibitors; Kinases; Lung cancer; Lung diseases; Lung Neoplasms - metabolism; Medical research; Medicine; Metabolism; Metabolites; Monosaccharides; Mortality; Non-small cell lung cancer; Non-small cell lung carcinoma; Oxidative stress; Oxygen; Pharmacology; Physiological aspects; Reactive oxygen species; Respiratory system agents; Ribose; Small cell lung cancer; Studies; Toxicology; Tumor cell lines; Vitamin C; United States > US; Kentucky
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0067081

Ascorbic acid (AA) exhibits significant anticancer activity at pharmacologic doses achievable by parenteral administration that have minimal effects on normal cells. Thus, AA has potential uses as a chemotherapeutic agent alone or in combination with other therapeutics that specifically target cancer-cell metabolism. We compared the effects of AA and combinations of AA with the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO) on the viability of three non-small cell lung cancer (NSCLC) cell lines to the effects on an immortalized lung epithelial cell line. AA concentrations of 0.5 to 5 mM caused a complete loss of viability in all NSCLC lines compared to a <10% loss of viability in the lung epithelial cell line. Combinations of AA and 3-PO synergistically enhanced cell death in all NSCLC cell lines at concentrations well below the IC50 concentrations for each compound alone. A synergistic interaction was not observed in combination treatments of lung epithelial cells and combination treatments that caused a complete loss of viability in NSCLC cells had modest effects on normal lung cell viability and reactive oxygen species (ROS) levels. Combination treatments induced dramatically higher ROS levels compared to treatment with AA and 3-PO alone in NSCLC cells and combination-induced cell death was inhibited by addition of catalase to the medium. Analyses of DNA fragmentation, poly (ADP-ribose) polymerase cleavage, annexin V-binding, and caspase activity demonstrated that AA-induced cell death is caused via the activation of apoptosis and that the combination treatments caused a synergistic induction of apoptosis. These results demonstrate the effectiveness of AA against NSCLC cells and that combinations of AA with 3-PO synergistically induce apoptosis via a ROS-dependent mechanism. These results support further evaluation of pharmacologic concentrations of AA as an adjuvant treatment for NSCLC and that combination of AA with glycolysis inhibitors may be a promising therapy for the treatment of NSCLC.