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.
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
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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
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.
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
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.