JCT  Vol.4 No.8 , October 2013
Megadoses of Sodium Ascorbate Efficiently Kill HL60 Cells in Vitro: Comparison with Arsenic Trioxide
ABSTRACT

Arsenic Trioxide (ATO) is widely acknowledged as the treatment of choice for Acute Promyelocytic Leukemia (APL). It is a “two-sided” drug since it can induce differentiation or kill APL and other tumor cells according to the dosage. Part of the cytotoxic effects of ATO on APL cells is due to its pro-oxidant activity, a characteristic which ATO shares with a number of other compounds, including high doses of ascorbate (ASC). In a comparative investigation on the cytotoxic effects of both ATO and ASC on HL60 (APL) cell lines, in Vitro, we have been able to confirm the known cytotoxic effects of ATO, but, more importantly, we have demonstrated that ASC is significantly more effective than ATO, in killing these cancer cells in Vitro, when the concentrations are maintained within the millimolar (mM) range, i.e. the range of plasma concentrations at which ASC induces oxidative damage to tumor cells. Since these plasma levels can be reached only by the intravenous administration of high doses of ASC, we propose that intravenous high doses of ASC may represent a potentially revolutionary new approach in the management of APL.


Cite this paper
D. Mastrangelo, L. Massai, G. Fioritoni, A. Iacone, P. Bartolomeo, P. Accorsi, T. Bonfini, M. Muscettola and G. Grasso, "Megadoses of Sodium Ascorbate Efficiently Kill HL60 Cells in Vitro: Comparison with Arsenic Trioxide," Journal of Cancer Therapy, Vol. 4 No. 8, 2013, pp. 1366-1372. doi: 10.4236/jct.2013.48162.
References
[1]   L. K. Hillestad, “Acute Promyelocytic Leukemia,” Acta Medica Scandinavica, Vol. 159, No. 3, 1957, pp. 189-194. http://dx.doi.org/10.1111/j.0954-6820.1957.tb00124.x

[2]   R. P. Warrell Jr., H. de Thé, Z. Y. Wang and L. Degos, “Acute Promyelocytic Leukemia,” New England Journal of Medicine, Vol. 329. 1993, pp. 177-189. http://dx.doi.org/10.1056/NEJM199307153290307

[3]   D. Nowak, D. Stewart and H. P. Koeffler, “Differentiation Therapy of Leukemia: 3 Decades of Development,” Blood, Vol. 113, No. 16, 2009, pp. 3655-3665. http://dx.doi.org/10.1182/blood-2009-01-198911

[4]   K. H. Antman, “Introduction: The History of Arsenic Trioxide in Cancer Therapy,” The Oncologist, Vol. 6, Suppl. 2, 2001, pp. 1-2. http://dx.doi.org/10.1634/theoncologist.6-suppl_2-1

[5]   B. L. Powell, “Arsenic Trioxide in Acute Promyelocytic Leukemia: Potion Not Poison,” Expert Reviews in Anticancer Therapy, Vol. 11, No. 9, 2011, pp. 1317-1319. http://dx.doi.org/10.1586/era.11.128

[6]   M. A. Sanz, D. Grimwade, M. S. Tallman, et al., “Management of Acute Promyelocytic Leukemia: Recommendations from an Expert Panel on Behalf of the European Leukemia Net,” Blood, Vol. 113, No. 9, 2009, pp. 1875-1891. http://dx.doi.org/10.1182/blood-2008-04-150250

[7]   Y. Rao, R. H. Li and D. Q. Zhang, “A Drug from Poison: How the Therapeutic Effect of Arsenic Trioxide on Acute Promyelocytic Leukemia Was Discovered,” Science China Life Science, Vol. 56, No. 6, 2013, pp. 495-502. http://dx.doi.org/10.1007/s11427-013-4487-z

[8]   J. Q. Mi, J. M. Li, S. X. Shen, S. J. Chen and Z. Chen, “How to Manage Acute Promyelocytic Leukemia,” Leukemia, Vol. 26, No. 8, 2012, pp. 1743-1751. http://dx.doi.org/10.1038/leu.2012.57

[9]   S. J. Chen, G. B. Zhou, S. W. Zhang, J. H. Mao, H. de Thé and Z. Chen, “From an Old Remedy to a Magic Bullet: Molecular Mechanisms Underlying the Therapeutic Effects of Arsenic in Fighting Leukemia,” Blood, Vol. 117, No. 24, 2011, pp. 6425-6437. http://dx.doi.org/10.1182/blood-2010-11-283598

[10]   C. Yedjou, P. Tchounwou, J. Jenkins and R. McMurray, “Basic Mechanisms of Arsenic Trioxide (ATO)-Induced Apoptosis in Human Leukemia (HL60) Cells,” Journal of Hematology and Oncology, Vol. 3, No. 28, 2010, pp. 1-9.

[11]   J. H. Kim, J. H. Kim, Y. S. Yu, D. H. Kim, C. J. Kim and K. W. Kim, “Antitumor Activity of Arsenic Trioxide on Retinoblastoma: Cell Differentiation and Apoptosis Depending on Arsenic Trioxide Concentration,” Investigative Ophthalmology and Visual Sciences, Vol. 50, No. 4, 2009, pp. 1819-1823. http://dx.doi.org/10.1167/iovs.08-2623

[12]   A. Emadi and S. D. Gore, “Arsenic Trioxide: An Old Drug Rediscovered,” Blood, Vol. 24, No. 4, 2010, pp. 191-199.

[13]   S. Alarifi, D. Ali, S. Alkahtani, M. A. Siddiqui and B. A. Ali, “Arsenic Trioxide-Mediated Oxidative Stress and Genotoxicity in Human Hepatocellular Carcinoma Cells,” OncoTargets and Therapy, Vol. 6, 2013, pp. 65-84.

[14]   R. C. Sun, P. G. Board and A. C. Blackburn, “Targeting Metabolism with Arsenic Trioxide and Dichloroacetate in Breast Cancer Cells, Oxidative Damage to Cancer Cells,” Molecular Cancer, Vol. 10, No. 142, 2011, pp. 1-15.

[15]   J. Zhou, J. Ye, X. Zhao, A. Li and J. Zhou, “JWA Is Required for Arsenic Trioxide Induced Apoptosis in HeLa and MCF-7 Cells via Reactive Oxygen Species and Mitochondria Linked Signal Pathway,” Toxicology and Applied Pharmacology, Vol. 230, No. 1, 2008, pp. 33-40. http://dx.doi.org/10.1016/ j.taap.2008.01.041

[16]   S. Ohno, Y. Ohno, N. Suzuki, G. I. Soma and M. Inoue, “High-Dose Vitamin C (Ascorbic Acid) Therapy in the Treatment of Patients with Advanced Cancer,” Anticancer Research, Vol. 29, 2009, pp. 809-816.

[17]   Q. Chen, M. Graham Espey, M. C. Krishna, et al., “Pharmacologic Ascorbic Acid Concentrations Selectively Kill Cancer Cells: Action as a Pro-Drug to Deliver Hydrogen Peroxide to Tissues,” Proceedings of the National Academy of Sciences, Vol. 102, No. 38, 2005, pp. 13604-13609. http://dx.doi.org/10.1073/pnas.0506390102

[18]   Q. Chen, M. G. Espey, A. Y. Sun, et al., “Pharmacologic Doses of Ascorbate Act as a Prooxidant and Decrease Growth of Aggressive Tumor Xenografts in Mice,” Proceedings of the National Academy of Sciences, Vol. 105, No. 32, 2008, pp. 11105-11109. http://dx.doi.org/10.1073/pnas.0804226105

[19]   P. Chen, J. Yu, B. Chalmers, et al., “Pharmacological Ascorbate Induces Cytotoxicity in Prostate Cancer Cells through ATP Depletion and Induction of Autophagy,” Anticancer Drugs, Vol. 23, No. 4, 2012, pp. 437-444. http://dx.doi.org/10.1097/CAD.0b013e32834fd01f

[20]   P. Chen, J Stone, G Sullivan, J. A. Drisko and Q. Chen, “Anti-Cancer Effect of Pharmacologic Ascorbate and Its Interaction with Supplementary Parenteral Glutathione in Preclinical Cancer Models,” Free Radicals in Biology and Medicine, Vol. 51, No. 3, 2011, pp. 681-687. http://dx.doi.org/10.1016/j. freeradbiomed.2011.05.031

[21]   D. Mastrangelo, L. Massai, L. Micheli, M. Muscettola, G. Cevenini and G. Grasso, “High Doses of Ascorbate Kill Y79 Retinoblastoma Cells in Vitro,” Journal of Clinical and Experimental Ophthalmolology, Vol. 4, No. 1, 2013, pp. 1-8.

[22]   W. Strober, “Trypan Blue Exclusion Test of Cell Viability,” Current Protocols in Immunology, 2001, Appendix 3: Appendix 3B.

[23]   M. J. Stoddart, “Cell Viability Assays: Introduction,” Methods in Molecular Biology, Vol. 740, 2011, pp. 1-6. http://dx.doi.org/10.1007/978-1-61779-108-6_1

[24]   D. Lu, X. C. Bai, L. Gui, et al., “Hydrogen Peroxide in the Burkitt’s Lymphoma Cell Line Raji Provides Protection against Arsenic Trioxide-Induced Apoptosis via the Phosphoinositide-3 Kinase Signalling Pathway,” British Journal of Haematology, Vol. 125, No. 4, 2004, pp. 512-520. http://dx.doi.org/10.1111/j.1365-2141.2004.04940.x

[25]   Y. J. Lee and E. Shacter, “Oxidative Stress Inhibits Apoptosis in Human Lymphoma Cells,” Journal of Biological Chemistry, Vol. 274, No. 28, 1999, pp. 19792-19798. http://dx.doi.org/10.1074/jbc. 274.28.19792

[26]   Z. Y. Wang and Z. Chen, “Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable,” Blood, Vol. 11, No. 5, 2008, pp. 2505-2515. http://dx.doi.org/10.1182/blood-2007-07-102798

[27]   H. de Thé, M. Le Bras and V. Lallemand-Breitenbach, “Acute Promyelocytic Leukemia, Arsenic, and PML Bodies,” Journal of Cell Biology, Vol. 198, No. 1, 2012, pp. 11-21. http://dx.doi.org/10.1083/jcb. 201112044

[28]   V. Selvaraj, M. Yeager-Armstead and E. Murray, “Protective and Antioxidant Role of Selenium on Arsenic Trioxide-Induced Oxidative Stress and Genotoxicity in the Fish Hepatoma Cell Line PLHC-1,” Environmental Toxicology and Chemistry, Vol. 31, No. 12, 2012, pp. 2861-2869. http://dx.doi.org/ 10.1002/etc.2022

[29]   Y. Sanchez, D. Amràn, E. de Blas and P. Aller, “Arsenic Trioxide as an Antitumor Agent: Mechanisms of Action and Strategies of Sensitization,” Journal of Applied Biomedicine, Vol. 8, 2010, pp. 199-208.

[30]   B. Halliwell, “Oxidative Stress and Cancer: Have We Moved Forward?” Review Article, Biochemical Journal, Vol. 411, 2007, pp. 1-11.

[31]   J. Verrax, H. Taper and P. Buc Calderon, “Targeting Cancer Cells by an Oxidant-Based Therapy,” Current Molecular Pharmacolology, Vol. 1, 2008, pp. 80-92.

[32]   A. Szent-Gyorgyi, “Observations on the Function of Peroxidase Systems and the Chemistry of the Adrenal Cortex: Description of a New Carbohydrate Derivative,” Biochemical Journal, Vol. 22, 1928, pp. 1387-1409.

[33]   S. J. Padayatty and M. Levine, “Reevaluation of Ascorbate in Cancer Treatment: Emerging Evidence, Open Minds and Serendipity,” Journal of the American College of Nutrition, Vol. 19, No. 4, 2000, pp. 423-425. http://dx.doi.org/10.1080/07315724.2000.10718941

[34]   W. J. McCormick, “Cancer: The Preconditioning Factor in Pathogenesis; A New Etiologic Approach,” Archives of Pediatrics, Vol. 71, 1954, pp. 313-322.

[35]   W. J. McCormick, “Cancer: A Collagen Disease, Secondary to a Nutritional Deficiency,” Archives of Pediatrics, Vol. 76, 1959, pp. 166-171.

[36]   E. Cameron and D. Rotman, “Ascorbic Acid, Cell Proliferation, and Cancer,” The Lancet, Vol. 299, No. 7749, 1972, p. 542. http://dx.doi.org/10.1016/S0140-6736(72)90215-2

[37]   C. G. Moertel, T. R. Fleming, E. T. Creagan, et al., “High-Dose Vitamin C versus Placebo in the Treatment of Patients with Advanced Cancer Who Have Had No Prior Chemotherapy: A Randomized Double-Blind Comparison,” New England Journal of Medicine, Vol. 312, No. 3, 1985, 137-141. http://dx.doi.org/10.1056/NEJM198501173120301

[38]   S. J. Padayatty, A. Y. Sun, Q. Chen, M. G. Espey, J. Drisko and M. Levine, “Vitamin C: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects,” PLoS ONE, Vol. 5, No. 7, 2010, Article ID: e11414. http://dx.doi.org/10.1371/journal.pone.0011414

[39]   M. Levine, C. Conry-Cantilena, Y. Wang, et al., “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, Vol. 93, No. 8, 1996, pp. 3704-3709. http://dx.doi.org/10.1073/ pnas.93.8.3704

[40]   J. Verrax and P. B. Calderon, “Pharmacologic Concentrations of Ascorbate Are Achieved by Parenteral Administration and Exhibit Antitumoral Effects,” Free Radicals in Biology and Medicine, Vol. 47, No. 1, 2009, pp. 32-40. http://dx.doi.org/10.1016/j.freeradbiomed.2009.02.016

[41]   S. J. Padayatty, H. Sun, Y. Wang, et al., “Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use,” Annals of Internal Medicine, Vol. 140, No. 7, 2004, pp. 533-537. http://dx.doi.org/10.7326/0003-4819-140-7-200404060-00010

[42]   B. Frei and S. Lawson, “Vitamin C and Cancer Revisited,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 32, 2008, pp. 11037-11038. http://dx.doi.org/10.1073/pnas.0806433105

[43]   D. A. Monti, E. Mitchell, A. J. Bazzan, et al., “Phase I Evaluation of Intravenous Ascorbic Acid in Combination with Gemcitabine and Erlotinib in Patients with Metastatic Pancreatic Cancer,” PLoS ONE, Vol. 7, No. 1 2012, Article ID: e29794. http://dx.doi.org/10.1371/journal.pone.0029794

[44]   T. Bachleitner-Hofmann, B. Gisslinger, E. Grumbeck and H. Gisslinger, “Arsenic Trioxide and Ascorbic Acid: Synergy with Potential Implications for the Treatment of Acute Myeloid Leukaemia?” British Journal of Haematology, Vol. 112, No. 3, 2001, pp. 783-786. http://dx.doi.org/10.1046/j.1365-2141.2001.02608.x

[45]   N. Karasavvas, J. M. Carcamo, G. Stratis and D. W. Golde, “Vitamin C Protects HL60 and U266 Cells from Arsenic Toxicity,” Blood, Vol. 105, No. 10, 2005, pp. 4004-4012. http://dx.doi.org/10.1182/ blood-2003-03-0772

[46]   M. L. Heaney, J. R. Gardner, N. Karasavvas, et al., “Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs,” Cancer Research, Vol. 66, No. 19, 2008, pp. 8031-8038. http://dx.doi.org/ 10.1158/0008-5472.CAN-08-1490

 
 
Top