Synergistic Antitumor Activity of Vitamins C and K3 on Human Bladder Cancer Cell Lines


Exponentially growing cultures of human bladder tumor cells (RT4 and T24) were treated with Vitamin C (VC) alone, Vitamin K3 (VK3) alone, or with a VC:VK3 combination continuously for 5 days or treated with vitamins for 1 h, washed with PBS and then incubated in culture medium for 5 days. Co-administration of the vitamins enhanced the antitumor activity 12- to 24-fold for the RT-4 cells and 6- to 41-fold for the T24 cells. Flow cytometry of RT4 cells exposed to the vitamins revealed a growth arrested population and a population undergoing cell death. Growth arrested cells were blocked near the G0/G1-S-phase interface, while cell death was due to autoschizis. Catalase treatment abrogated both cell cycle arrest and cell death which implicated hydrogen peroxide (H2O2) in these processes. The H2O2 production resulted in a moderate increase in lipid peroxidation and depletion of cell thiol levels. Analysis of cellular ATP levels revealed a transient increase in ATP production for VC and the VC:VK3 combination, but decreased ATP levels following VK3 treatment. Lipid peroxidation, thiol depletion and ATP modulation occurred at a 17-fold lower concentration in the vitamin combination than with either vitamin alone. These results suggested that the increased cytotoxicity of the vitamin combination was due to redox cycling and increased oxidative stress.

Share and Cite:

K. McGuire, J. Jamison, J. Gilloteaux and J. Summers, "Synergistic Antitumor Activity of Vitamins C and K3 on Human Bladder Cancer Cell Lines," Journal of Cancer Therapy, Vol. 4 No. 6C, 2013, pp. 7-19. doi: 10.4236/jct.2013.46A3002.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] R. Siegel, D. Naishadham and A. Jemal, “Cancer Statistics, 2013,” CA: A Cancer Journal for Clinicians, Vol. 63, No. 1, 2013, pp. 11-30. doi:10.3322/caac.21166
[2] P. J. Goebell and M. A. Knowles, “Bladder Cancer or Bladder Cancers? Genetically Distinct Malignant Conditions of the Urothelium,” Urologic Oncology, Vol. 28, No. 4, 2010, pp. 409-428.
[3] Y. Li, K. Izumi and H. Miyamoto, “The Role of the Androgen Receptor in the Development and Progression of Bladder Cancer,” The Japanese Journal of Clinical Oncology, Vol. 42, No. 7, 2012, pp. 569-577. doi:10.1093/jjco/hys072
[4] C. Logan, M. Brown and D. Hayne, “Intravesical Therapies for Bladder Cancer-Indications and Limitations,” British Journal of Urology International, Vol. 110, No. S4, 2012, pp. 12-21.
[5] A. Pawinski, R. Sylvester, K. H. Kurth, et al., “A Combined Analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council Randomized Clinical Trials for the Prophylactic Treatment of Stage TaT1 Bladder Cancer,” The Journal of Urology, Vol. 156, No. 6, 1996, pp. 1934-1941.
[6] C. N. Sternberg, A. Yagoda, H. I. Scher, et al., “Methotrexate, Vinblastine, Doxorubicin, and Cisplatin for Advanced Transitional Cell Carcinoma of the Urothelium. Efficacy and Patterns of Response and Relapse,” Cancer Vol. 64, No. 12, 1989, pp. 2448-2458. doi:10.1002/1097-0142(19891215)64:12<2448::AID-CNCR2820641209>3.0.CO;2-7
[7] F. Calabrò and C. N. Sternberg, “Metastatic Bladder Cancer: Anything New?” Current Opinion in Supportive and Palliative Care. Vol. 6, No. 3, 2012, pp. 304-309.
[8] H. von der Maase, S. W. Hansen, J. T. Roberts, et al., “Gemcitabine and Cisplatin versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational, Multicenter, Phase III Study,” Journal of Clinical Oncology, Vol. 17, No. 17, 2000, pp. 3068-3077.
[9] M. Hussain, U. Vaishampayan, W. Du, et al., “Combination Paclitaxel, Carboplatin, and Gemcitabine Is an Active Treatment for Advanced Urothelial Cancer,” Journal of Clinical Oncology, Vol. 19, No. 9, 2001, pp. 2527-2533.
[10] K. D. Sievert, B. Amend, U. Nagele, et al., “Economic Aspects of Bladder Cancer: What Are the Benefits and Costs?” World Journal of Urology, Vol. 27, No. 3, 2009, pp. 295-300. doi:10.1007/s00345-009-0395-z
[11] D. L. Lamm and M. Allaway, “Current Trends in Bladder Cancer Treatment,” Annales Chirurgiae et Gynaecologiae, Vol. 89, 2000, pp. 234-241.
[12] D. L. Lamm, D. R. Riggs, J. S. Shriver, et al., “Megadose Vitamins in Bladder Cancer: A Double-Blind Clinical Trial,” The Journal of Urology, Vol. 151, No. 1, 1994, pp. 21-26.
[13] R. Bonilla-Porras, M. Jimenez-Del-Rio and C. VelezPardo, ”Vitamin K3 and Vitamin C Alone or in Combination Induced Apoptosis in Leukemia Cells by a Similar Oxidative Stress Signalling Mechanism,” Cancer Cell International, Vol. 11, No. 10, 2011, p. 19. doi:10.1186/1475-2867-11-19
[14] J. Verrax, S. Vanbever, J. Stockis, et al., “Role of Glycolysis Inhibition and Poly(ADP-ribose) Polymerase Activation in Necrotic-Like Cell Death Caused by Ascorbate/ Menadione-Induced Oxidative Stress in K562 Human Chronic Myelogenous Leukemic Cells,” International Journal of Cancer, Vol. 120, No. 6, 2007, pp. 1192-1197. doi:10.1002/ijc.22439
[15] J. Verrax, J. Stockis, A. Tison, et al., “Oxidative Stress by Ascorbate/Menadione Association Kills K562 Human Chronic Myelogenous Leukaemia Cells and Inhibits Its Tumour Growth in Nude Mice,” Biochemical Pharmacology, Vol. 72, No. 6, 2006, pp. 671-680. doi:10.1016/j.bcp.2006.05.025
[16] J. Verrax, M. Delvaux, N. Beghein, et al., “Enhancement of Quinone Redox Cycling by Ascorbate Induces a Caspase-3 Independent Cell Death in Human Leukemia Cells. An in Vitro Comparative Study,” Free Radical Research, Vol. 39, No. 6, 2005, pp. 649-657. doi:10.1080/10715760500097906
[17] M. Venugopal, J. M. Jamison, J. Gilloteaux, et al., “Synergistic Antitumor Activity of Vitamins C and K3 on Human Urologic Tumor Cell Lines,” Life Sciences, Vol. 56, No. 17, 1996, pp. 1389 1400. doi:10.1016/0024-3205(96)00466-3
[18] J. Gilloteaux, J. M. Jamison, E. Ervin, et al., “Scanning Electron Microscopy and Transmission Electron Microscopy Aspects of the Synergistic Antitumor Activity of Vitamin C/ Vitamin K3 Combinations against Human T24 Bladder Carcinoma: Another Kind of Cell Death?” Scanning, Vol. 20, No. 3, 1998, pp. 208 209.
[19] E. Ervin, J. M. Jamison, J. Gilloteaux, et al., “Characterization of the Early Events in Vitamin C and K3 Induced Death of Human Bladder Tumor Cells,” Scanning, Vol. 20, No. 3, 1998, pp. 210 211.
[20] J. Gilloteaux, J. M. Jamison, D. Arnold, et al., “Cancer Cell Necrosis by Autoschizis: Synergism of Antitumor Activity of Vitamin C:Vitamin K3 on Human Bladder Carcinoma T24 Cells,” Scanning, Vol. 20, No. 3, 1998, pp. 564 576.
[21] J. Gilloteaux, J. M. Jamison, D. Arnold, et al., “Autoschizis: Another Cell Death for Cancer Cells Induced by Oxidative Stress,” In Advances in Microanatomy of Cells and Tissues, Biophysical and Biochemical Correlates, Marcello Malphigi Series, Italian Journal of Anatomy and Embryology, Vol. 106, No. 2, 2001, pp. 79-91.
[22] J. Gilloteaux, J. M. Jamison, D. Arnold, H. S. Taper, J. L. Summers, “Ultrastructural Aspects of Autoschizis: A New Cancer Cell Death induced by the Synergistic Action of Ascorbate/Menadione on Human Bladder Carcinoma Cells,” Ultrastructural Pathology, Vol. 25, No. 3, 2001, pp. 183-192. doi:10.1080/019131201300343810
[23] J. M. Jamison, J. Gilloteaux, H. S. Taper, et al., “Autoschizis: A Novel Cell Death,” Biochemical Pharmacology, Vol. 63, No. 10, 2002, pp. 1773-1783. doi:10.1016/S0006-2952(02)00904-8
[24] J. M. Jamison, J. Gilloteaux, M. R. Nassiri, et al., “Induction of Cell Cycle Arrest and Autoschizis in a Human Bladder Carcinoma Cell Line by Vitamins C and K3,” Biochemical Pharmacology, Vol. 67, No. 2, 2004, pp. 337-351. doi:10.1016/j.bcp.2003.08.040
[25] J. Gilloteaux, J. M. Jamison, D. Arnold, et al., “Morphology and DNA Degeneration during Autoschizic Cell Death in Bladder Carcinoma T24 Cells Induced by Ascorbate and Menadione Treatment,” Anatomical Record, Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology, Vol. 288, No. 1, 2006, pp. 58-83. doi:10.1002/ar.a.20276
[26] J. Gilloteaux, J. M. Jamison, D. R. Neal, et al., “Cell Damage and Death by Autoschizis in Human Bladder (RT4) Carcinoma Cells Resulting from Treatment by Ascorbate and Menadione,” Ultrastructural Pathology, Vol. 34, No. 3, 2010, pp. 140-160. doi:10.3109/01913121003662304
[27] J. M. Jamison, J. Gilloteaux, L. Perlaky, et al., “Nucleolar Changes and Fibrillarin Redistribution Following Apatone? Treatment of Human Bladder Carcinoma Cells,” Journal of Histochemistry and Cytochemistry, Vol. 58, No. 7, 2010, pp. 635-652. doi:10.1369/jhc.2010.956284
[28] W. Kassouf, R. Highshaw, G. M. Nelkin, et al., “Vitamins C and K3 Sensitize Human Urothelial Tumors to Gemcitabine,” The Journal of Urology, Vol. 176, No. 4, 2006, pp. 1642-1647.
[29] R. Beck, J. Verrax, N. Dejeans, et al., “Menadione Reduction by Pharmacological Doses of Ascorbate Induces an Oxidative Stress That Kills Breast Cancer cells,” International Journal of Toxicology, Vol. 28, No. 1, 2009, pp. 33-42. doi:10.1177/1091581809333139
[30] H. S. Taper, “Reversibility of Acid and Alkaline Deoxyribonuclease Deficiency in Malignant Tumor Cells,” Journal of Histochemistry and Cytochemistry, Vol. 29, No. 9, 1981, pp. 1053-1060.
[31] M. F. Vita, N. Nagachar, D. Avramidis, et al., “Pankiller Effect of Prolonged Exposure to Menadione on Glioma Cells: Potentiation by Vitamin C,” Investigational New Drugs, Vol. 82, No. 11, 2011, p. 1314. doi:10.1007/s10637-010-9489-0
[32] D. Arnold, J. Gilloteaux, J. Jamison, et al., “Synergistic Effect of Vitamin C and Vitamin K3 on Human Renal Adenocarcinoma Cell Line (Caki 1): Scanning Electron Microscopy,” Scanning, Vol. 21, No. 2, 1999, pp. 109 110.
[33] J. Verrax, R. Beck, N. Dejeans, et al., “Redox-Active Quinones and Ascorbate: An Innovative Cancer Therapy That Exploits the Vulnerability of Cancer Cells to Oxidative Stress,” Anti-Cancer Agents in Medicinal Chemistry, Vol. 11, No. 2, 2011, pp. 213-221. doi:10.2174/187152011795255902
[34] H. S. Taper, J. de Gerlache, M. Lans M, et al., “NonToxic Potentiation of Cancer Chemotherapy by Combined C and K3 Vitamin Pretreatment,” International Journal of Cancer, Vol. 40, No. 4, 1987, pp. 575-579. doi:10.1002/ijc.2910400424
[35] H. S. Taper, A. Keyeux and M. Roberfroid, “Potentiation of Radiotherapy by Non-Toxic Pretreatment with Combined Vitamin C and K3 in Mice Bearing Solid, Transplantable Tumor,” Anticancer Research Vol. 16, No. 1, 1996, pp. 499-503.
[36] H. S. Taper and M. Roberfroid, “Non-Toxic Sensitization of Cancer Chemotherapy by Combined C and K3 Vitamin Pretreatment in a Mouse Tumor Resistant to Oncovin,” Anticancer Research, Vol. 12, No. 5, 1992, pp. 1651-1654.
[37] H. S. Taper, J. M. Jamison, J. Gilloteaux, et al., “Inhibition of the Development of Metastases by Dietary Vitamin C: K3 Combination,” Life Sciences, Vol. 75, No. 8, 2004, pp. 955-967. doi:10.1016/j.lfs.2004.02.011
[38] M. F. Chen, C. M. Yang and C. M. Su, “Inhibitory Effect of Vitamin C in Combination with Vitamin K3 on Tumor Growth and Metastasis of Lewis Lung Carcinoma Xenografted in C57BL/6 Mice,” Nutrition and Cancer, Vol. 63, No. 7, 2011, pp. 1036-1043. doi:10.1080/01635581.2011.597537
[39] J. Gilloteaux, J. M. Jamison, D. Arnold, et al., “Microscopic Aspects of Autoschizic Cell Death in Human Ovarian Carcinoma (2774) Cells Following Vitamin C, Vitamin K3 or Vitamin C:K3 Treatment,” Microscopy and Microanalysis, Vol. 9, No. 4, 2003, pp. 311-329. doi:10.1017/S1431927603030125
[40] J. Gilloteaux, J. M. Jamison, D. Arnold, et al., “Autoschizis of Human Ovarian Carcinoma Cells: Scanning Electron and Light Microscopy of a New Cell Death Induced by Sodium Ascorbate: Menadione Treatment,” Scanning, Vol. 25, No. 3, 2003, pp. 137-149. doi:10.1002/sca.4950250306
[41] V. E. Von Gruenigen, J. M. Jamison, J. Gilloteaux, et al., “The in Vitro Antitumor Activity of Vitamins C and K3 against Ovarian Carcinoma,” Anticancer Research, Vol. 23, No. 4, 2003, pp. 3279-3287.
[42] J. Gilloteaux, J. M. Jamison, D. Arnold, et al., “Autoschizis: A New Form of Cell Death for Human Ovarian Carcinoma Cells Following Ascorbate: Menadione Treatment: Nuclear and DNA Degradation,” Tissue and Cell, Vol. 36, No. 3, 2004, pp. 197-209. doi:10.1016/j.tice.2004.01.006
[43] J. Gilloteaux, J. M. Jamison, M., Venugopal, et al., “Scanning Electron Microscopy and Transmission Electron Microscopy Aspects of Synergistic Antitumor Activity of Vitamin C Vitamin K3 Combinations against Human Prostatic Carcinoma Cells,” Scanning Microscopy, Vol. 9, No. 1, 1995, pp. 159 173.
[44] J. M. Jamison, J. Gilloteaux, M. Venugopal, et al., “Flow Cytometric and Ultrastructural Aspects of the Synergistic Antitumor Activity of Vitamin C Vitamin K3 Combinations against Human Prostatic Carcinoma Cells,” Tissue and Cell, Vol. 28, No. 6, 1996, pp. 687 701.
[45] M. Venugopal, J. M. Jamison, J. Gilloteaux, J. A. Koch, M. Summers, J. Hoke, C. Sowick and J. L. Summers, “Synergistic Antitumor Activity of Synergistic Antitumor Activity of Vitamin C and K3 against Human Prostate Carcinoma Cell Lines,” Cell Biology International Reports, Vol. 20, No. 12, 1996, pp. 787 797.
[46] H. S. Taper, J. M. Jamison, J. Gilloteaux, et al., “In Vivo Reactivation of DNases in Implanted Human Prostate Tumors Following Administration of a Vitamin C/K3 Combination,” Journal of Histochemistry and Cytochemistry, Vol. 49, No. 1, 2001, pp. 109-120. doi:10.1177/002215540104900111
[47] J. M. Jamison, J. Gilloteaux, H. S. Taper, et al., “Evaluation of the In Vitro and In Vivo Antitumor Activities of Vitamin C and K3 Combinations against Human Prostate Cancer,” Journal of Nutrition, Vol. 131, No. 1, 2001, pp. 158S-160S.
[48] P. B. Calderon, J. Cadrobbi, C. Marques, et al., “Potential Therapeutic Application of the Association of Vitamins C and K3 in Cancer Treatment,” Current Medicinal Chemistry, Vol. 9, No. 24, 2003, pp. 2269-2285.
[49] J. Verrax, J. Cadrobbi, M. Delvaux, et al., “The Association of Vitamins C and K3 Kills Cancer Cells Mainly by Autoschizis, a Novel Form of Cell Death. Basis for Their Potential Use as Coadjuvants in Anticancer Therapy,” European Journal of Medicinal Chemistry, Vol. 38, No. 5, 2003, pp. 451-457. doi:10.1016/S0223-5234(03)00082-5
[50] J. M. Jamison, J. Gilloteaux, H. S. Taper, et al., “The in Vitro and in Vivo Antitumor Activity of Vitamin C: K3 Combinations against Prostate Cancer,” In: J. L. Lucas, Ed., Prostate Cancer, Nova Science Publishers, Inc., New York, 2005, pp. 189-236.
[51] B. Tareen, J. L. Summers, J. M. Jamison, et al., “A 12 Week, Open Label, Phase I/IIa Study Using Apatone? for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy,” International Journal of Medical Science, Vol. 5, No. 2, 2008, pp. 62-67. doi:10.7150/ijms.5.62
[52] J. Gilloteaux, J. M. Jamison, D. Arnold, et al., “Autoschizis: A New Cell Death Found in Tumour Cells Induced by an Oxidative Stress Mechanism,” In: A. Méndez-Vilas and J. Díaz, Eds., Microscopy: Science, Technology, Applications and Education, Formatex Research Center, Badajoz, 2010, pp. 1-12.
[53] J. Gilloteaux, J. M. Jamison, D. R. Neal, et al., “Xenotransplanted Human Prostate Carcinoma (DU145) Cells Develop into Carcinomas and Cribriform Carcinomas: Ultrastructural Aspects,” Ultrastructural Pathology, Vol. 36, No. 5, 2012, pp. 294-311. doi:10.3109/01913123.2012.708472
[54] J. Gilloteaux, J. M. Jamison, D. R. Neal, et al., “Human Prostate DU145 Carcinoma Cells Implanted in Nude Mice Remove the Peritoneal Mesothelium to Invade and Grow as Carcinomas,” The Anatomical Record, Vol. 296, No. 1, 2013, pp. 40-55. doi:10.1002/ar.22607
[55] E. Lasalvia-Prisco, S. Cucchi, J. Vázquez, et al., “Serum Markers Variation Consistent with Autoschizis Induced by Ascorbic Acid-Menadione in Patients with Prostate Cancer,” Medical Oncology, Vol. 20, No. 1, 2003, pp. 45-52. doi:10.1385/MO:20:1:45
[56] D. B. Agus, J. C. Vera and D. W. Golde, “Stromal Cell Oxidation: A Mechanism by Which Tumors Obtain Vitamin C,” Cancer Research, Vol. 59, No. 18, 1999, pp. 4555-4558.
[57] B. Meier, A. R. Cross, J. T. Hancock, et al., “Identification of a Superoxide Generating NADPH Oxidase System in Human Fibroblasts,” Biochemical Journal, Vol. 275, No. 1, 1991, pp. 241-245.
[58] J. C. Vera, C. I. Rivas, J. Fischbarg, et al., “Mammalian Facilitative Hexose Transporters Mediate the Transport of Dehydroascorbic Acid,” Nature, Vol. 364, No. 6432, 1993, pp. 79-82. doi:10.1038/364079a0
[59] J. C. Vera, C. I. Rivas, F. V. Velasquez, et al., “Resolution of the Facilitated Transport of Dehydroascorbic Acid from Its Intracellular Accumulation as Ascorbic Acid,” The Journal of Biological Chemistry, Vol. 270, No. 40, 1995, pp. 23706-23712.
[60] M. M. Bradford, “A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding,” Analytical Biochemistry, Vol. 72, No. 1-2, 1976, pp. 248-254. doi:10.1016/0003-2697(76)90527-3
[61] J. A. Buege and S. D. Aust, “Microsomal Lipid Peroxidation,” Methods in Enzymology, Vol. 52, 1978, pp. 302-310. doi:10.1016/S0076-6879(78)52032-6
[62] K. Nitahara, A. Kittel, S. D. Liang, et al., “A1-ReceptorMediated Effect of Adenosine on the Release of Acetylcholine from the Myenteric Plexus: Role and Localization of Ecto-ATPase and 5’-Nucleotidase,” Neuroscience, Vol. 67, No. 1, 1995, pp. 159-168. doi:10.1016/0306-4522(94)00585-S
[63] J. F. Nagelkerke, P. Dogterom, H. J. De Bont, et al., “Prolonged High Intracellular Free Calcium Concentrations Induced by ATP Are Not Immediately Cytotoxic in Isolated Rat Hepatocytes,” Biochemical Journal, Vol. 263, No. 2, 1989, pp. 347-353.
[64] M. J. González, J. R. Miranda-Massari, E. M. Mora, et al., “Orthomolecular Oncology Review: Ascorbic Acid and Cancer 25 Years Later,” Integrative Cancer Therapies, Vol. 4, No. 1, 2005, pp. 32-44. doi:10.1177/1534735404273861
[65] J. B. Liehr, “Vitamin C Reduces the Incidence and Severity of Renal Tumors Induced by Estradiol and Diethylstilbesterol,” The American Journal of Clinical Nutrition, Vol. 54, No. 6, 1991, pp. 1256S-1260S.
[66] Y. Zaizen, A. Nakagawara and K. Ikeda, “Patterns of Destruction of Mouse Neuroblastoma Cells by Extracellular Hydrogen Peroxide Formed by 6-Hydroxydopamine and Ascorbate,” Journal of Cancer Research and Clinical Oncology, Vol. 111, No. 2, 1986, pp. 93-97. doi:10.1007/BF00400743
[67] J. J. Casciari, N. H. Riordan, T. L. Schmidt, et al., “Cytotoxicity of Ascorbate, Lipoic Acid, and Other Antioxidants in Hollow Fibre in Vitro Tumours,” British Journal of Cancer, Vol. 84, No. 11, 2001, pp. 1544-1550. doi:10.1054/bjoc.2001.1814
[68] G. J. Koch and J. E. Biaglow, “Toxicity, Radiation Sensitivity Modification and Biological Effects of Dehydroascorbate and Ascorbate in Mammalian Cells,” Journal of Cellular Physiology, Vol. 94, No. 3, 1978, pp. 299-306. doi:10.1002/jcp.1040940307
[69] L. M. Nutter, A. L. Cheng, H. I. Hung, et al., “Menadione: Spectrum of Anticancer Therapy and Effects on Nucleotide Metabolism in Human Neoplastic Cell Lines,” Biochemical Pharmacology, Vol. 41, No. 9, 1991, pp. 1283-1292. doi:10.1016/0006-2952(91)90099-Q
[70] W. C. Su, T. P. Sun and F. Y. Wu, “The in Vitro and in Vivo Cytotoxicity of Menadione (Vitamin K3) against Rat Transplantable Hepatoma Induced by 3’-Methyl-4-dimethyl-aminoazobenzene,” Gaoxiong Yi Xue Ke Xue Za Zhi, Vol. 7, No. 9, 1991, pp. 454-459.
[71] T. W. Gant, D. N. Rao, R. Mason, et al., “Redox Cycling and Sulphydryl Arylation; Their Relative Importance in the Mechanism of Quinone Cytotoxicity to Isolated Hepatocytes,” Chemico-Biological Interactions, Vol. 65, No. 2, 1988, pp. 157-173. doi:10.1016/0009-2797(88)90052-X
[72] F. Mirabelli, A. Salis, M. Vairetti, et al., “Cytoskeletal Alterations in Human Platelets Exposed to Oxidative Stress Are Mediated by Oxidative and Ca2+-Dependent Mechanisms,” Archives of Biochemistry and Biophysics, Vol. 270, No. 2, 1989, pp. 478-488. doi:10.1016/0003-9861(89)90529-8
[73] C. R. Stubberfield and C. R. Cohen, “Interconversion of NAD(H) to NADP(H): A Cellular Response to QuinoneInduced Oxidative Stress in Isolated Hepatocytes,” Biochemical Pharmacology, Vol. 38, No. 16, 1989, pp. 2631-2637. doi:10.1016/0006-2952(89)90548-0
[74] V. Noto, H. S. Taper, Y. H. Jiang, et al., “Effects of Sodium Ascorbate (Vitamin C) and 2-Methyl-1,4-naphthoquinone (Vitamin K3) Treatment on Human Tumor Cell Growth in Vitro, I: Synergism of Combined Vitamin C and K3 Action,” Cancer, Vol. 63, No. 5, 1989, pp. 901-906. doi:10.1002/1097-0142(19890301)63:5<901::AID-CNCR2820630518>3.0.CO;2-G
[75] W. De Loecker, J. Janssens, J. Bonte, et al., “Effects of Sodium Ascorbate (Vitamin C) and 2-Methyl-1,4-naphthoquinone (Vitamin K3) Treatment on Human Tumor Cell Growth in Vitro, II: Synergism with Combined Chemotherapy Action,” Anticancer Research, Vol. 13, No. 1, 1993, pp. 103-106.
[76] R. Jarabak and J. Jarabak, “Effect of Ascorbate on the DT-Diaphorase-Mediated Redox Cycling of 2-Methyl1,4-naphthoquinone,” Archives of Biochemistry and Biophysics, Vol. 318, No. 2, 1995, pp. 418-423. doi:10.1006/abbi.1995.1249
[77] M. Comporti, “Three Modes of Free Radical-Induced Cell Injury,” Chemico-Biological Interactions, Vol. 72, No. 1-2, 1989, pp. 1-56.
[78] D. Di Monte, G. Bellomo, H. Thor, et al., “MenadioneInduced Cytotoxicity Is Associated with Protein Thiol Oxidation and Alteration in Intracellular Ca2+ Homeostasis,” Archives of Biochemistry and Biophysics, Vol. 235, No. 2, 1984, pp. 343-350. doi:10.1016/0003-9861(84)90207-8
[79] J. M. Cárcamo, A. Pedraza, O. Bórquez-Ojeda, et al., “Vitamin C Suppresses TNF Alpha-Induced NF Kappa B Activation by Inhibiting I Kappa B Alpha Phosphorylation,” Biochemistry, Vol. 41, No. 43, 2002, pp. 12995-13002. doi:10.1021/bi0263210
[80] V. S. Akatov, Y. V. Evtodienko, V. V. Leshchenko, et al., “Combined Vitamins B12b and C Induce the Glutathione Depletion and the Death of Epidermoid Human Larynx Carcinoma Cells HEp-2,” Bioscience, Vol. 20, No. 5, 2000, pp. 411-417. doi:10.1023/A:1010386102562
[81] S. Biswas, X. Zhao, A. P. Mone, et al., “Arsenic Trioxide and Ascorbic Acid Demonstrate Promising Activity against Primary Human CLL Cells in Vitro,” Leukemia Research, Vol. 34, No. 7, 2010, pp. 925-931.
[82] H. Zhang, “Anticancer Activities of Resveratrol Alone and in Combination with Ascorbic Acid,” Master’s Thesis, Kent State University, Kent, 2010.
[83] S. Prakash, J. Sunitha and M. Hans, “Role of Coenzyme Q10 as an Antioxidant and Bioenergizer in Periodontal Diseases,” Indian Journal of Pharmacology, Vol. 42, No. 6, 2010, pp. 334-337. doi:10.4103/0253-7613.71884
[84] A. W. Linnane, M. Kios and L. Vitetta, et al., “Coenzyme Q(10)—Its Role as a Prooxidant in the Formation of Superoxide Anion/Hydrogen Peroxide and the Regulation of the Metabolome,” Mitochondrion, Vol. 7, 2007, pp. S51-S61. doi:10.1016/j.mito.2007.03.005
[85] V. A. Roginsky, G. Bruchelt and O. Bartuli, “Ubiquinone-0 (2,3-Dimethoxy-5-methyl-1,4-benzo-qui-none) as Effective Catalyzer of Ascorbate and Epinephrine Oxidation and Damager of Neuroblastoma Cells,” Biochemical Pharmacology, Vol. 55, No. 1, 1998, pp. 85-91. doi:10.1016/S0006-2952(97)00434-6
[86] C. Spielholz, D. W. Golde, A. N. Houghton, et al. “Increased Facilitated Transport of Dehydroascorbic Acid without Changes in Sodium-Dependent Ascorbate Transport in Human Melanoma Cells,” Cancer Research, Vol. 57, No. 12, 1997, pp. 2529-2537.
[87] K. M. McGuire, “Characterization of Apatone and Tolecine Induced Cell Death Mechanisms in Bladder and Ovarian Cancer,” Ph.D. Dissertation, Kent State University, Kent, 2012.
[88] L. Dyrskjot, M. Kruhoffer, T. Thykjaer, et al., “Gene Expression in the Urinary Bladder: A Common Carcinoma in Situ Gene Expression Signature Exists Disregarding Histopathological Classification,” Cancer Research, Vol. 64, No. 11, 2004, pp. 4040-4048. doi:10.1158/0008-5472.CAN-03-3620
[89] K. M. Owens, M. Kulawiec, M. M. Desouki, et al., “Impaired OXPHOS Complex III in Breast Cancer,” PLoS One, Vol. 6, No. 8, 2011, Article ID: e23846. doi:10.1371/journal.pone.0023846
[90] S. Eleff, N. G. Kennaway, N. R. M. Buist, et al., “31P NMR Study of Improvement in Oxidative Phosphorylation by Vitamins K3 and C in a Patient with a Defect in Electron Transport at Complex III in Skeletal Muscle,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 81, No. 11, 1984, pp. 3529-3533. doi:10.1073/pnas.81.11.3529

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.