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Pharmacological ascorbate triggers apoptotic pathway in liver cancer cells via up regulation of TNF-α

Research Paper | December 1, 2016

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Muhammad Imran Raza, Abeera Sikandar, Hajra Sadia

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Int. J. Biosci.9( 6), 253-258, December 2016

DOI: http://dx.doi.org/10.12692/ijb/9.6.253-258


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Ascorbic acid (Vitamin-C) is known to have tumor preventive and anti-tumor effects but the mechanism through which it regulates tumor progression needs to be elucidated. Probably, vitamin-C exerts its cytotoxic effects through TNFα mediated apoptotic pathway. TNFα induces two pathways simultaneously, that are, inflammatory and apoptotic pathways. In tumor cells the balance between apoptotic and inflammatory pathways is disturbed. TNFα induced NF-κB signaling is thought to be responsible for the inflammatory pathway and is implicated in many chronic diseases/disorders including cancer. Inhibition of inflammatory pathway at some point may allow only apoptotic pathway to proceed further, resulting in cancer cell death. This study was designed to evaluate the cytotoxic effect of ascorbic acid on Hepatocellular Carcinoma cells. Cell viability study was accessed after exposing the cells to increasing concentration of vitamin C. Expression of genes involved in signaling like TNFα and NF-κB was quantified. EC50 of Vitamin-C for Huh-7 was found to be 2.17mM. The expression profiling showed that TNFα was elevated, whereas the expression of NF-κB remained unchanged. In synthesis, the study showed that vitamin-C induced TNFα mediate apoptosis by shifting the balance from inflammatory to apoptotic pathway. These findings may be helpful in further understanding of the mechanism of cytotoxicity in cancer cells induced by high dose vitamin-C.


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Pharmacological ascorbate triggers apoptotic pathway in liver cancer cells via up regulation of TNF-α

Aggarwal BB, Shishodia S, Takada Y, Jackson-Bernitsas D, Ahn K, SethiG, Ichikawa H. 2006. Cytokines as potential therapeutic targets for inflammatory skin diseases. TNF blockade: An Inflammatory Issue.Ernest Schering Research Foundation Workshop 56, 161-186.

Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. 2006. Inflammation And Cancer: How Hot Is The Link. Biochemical Pharmacology 72, 1605-21.

Bowie A, O’neill LA. 2000. Oxidative Stress And Nuclear factor-kB activation: a reassessment of the evidence in the light of recent discoveries. Biochemical pharmacology 59, 13-23.

Cameron E, Pauling L. 1976. Supplemental Ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proceedings of the National Academy of Sciences 73, 3685-3689.

Campbell A, Jack T, Cameron E. 1991. Reticulum cell sarcoma: two complete spontaneous’ regressions, in response to high-dose ascorbic acid therapy. A report on subsequent progress. Oncology 48, 495-497.

Carr AC, Vissers MCM, Cook JS. 2014. The Effect of Intravenous Vitamin C on Cancer- and Chemotherapy-Related Fatigue and Quality of Life. Frontiers in Oncology 4, 283.

Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner, GR, Shacter E, Levine M. 2005. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proceedings of National Academy of Scences USA 102, 13604-9.

Eggermont AM, De Wilt JH, Ten Hagen TL. 2003. Current uses of isolated limb perfusion in the clinic and a model system for new strategies. The lancet Oncology 4, 429-437.

Graumlich JF, Ludden TM, Conry-Cantilena C, Cantilena LR, Wang Y, Levine M. Pharmacokinetic Model of Ascorbic Acid in Healthy Male Volunteers During Depletion and Repletion. Pharmaceutical Research 14, 1133-1139.

Hewamana S, Alghazal S, Lin TT, Clement M, Jenkins C, Guzman ML, Jordan CT, Neelakantan S, Crooks, PA, Burnett AK. 2008. The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target. Blood 111, 4681-4689.

Hoffer LJ, Robitaille L, Zakarian, Melnychuk D, Kavan P, Agulnik J, Cohen V, Small D, Miller WHJR. 2015. High-dose intravenous vitamin-C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PLoS One 10, e0120228.

Lee KM, Kang BS, Lee HL, Son SJ, Hwang SH, Kim DS, Park JS, Cho HJ. 2004. Spinal NF‐kB activation induces COX‐2 upregulation and contributes to inflammatory pain hypersensitivity. European Journal of Neuroscience 19, 3375-3381.

Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR. 1996. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proceedings of the National Academy of Sciences of the United States of America 93, 3704-3709.

Mcglynn KA, London WT. Epidemiology and natural history of hepatocellular carcinoma. Best Practice & Research Clinical Gastroenterology 19, 3-23.

Nakamoto T, Inagawa H, Takagi K, Soma G. 1999. A new method of antitumor therapy with a high dose of TNF perfusion for unresectable liver tumors. Anticancer Research 20, 4087-4096.

Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E,Ben-Neriah Y. 2004. NF-[kappa] B functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-466.

Robinson SC,Coussens LM. 2005. Soluble Mediators of Inflammation During Tumor Development. Advances in Cancer Research 93,    159-187.

Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM. 1996. Suppression of TNF-alpha-induced apoptosis by NF-kB. Science 274, 787.

Zhu BS, Xing, CG, Lin F, Fan XQ, Zhao K Qin ZH. 2011. Blocking NF-kB nuclear translocation leads to p53-related autophagy activation and cell apoptosis. World Journal of Gastroenterology 17, 478-487.