Abstract
The main feature of fast-growing malignant tumors is the Warburg-type metabolism, which is directly related to an extremely high quantity of hexokinase (HK) bound to the voltage-dependent anion channels (VDACs) in the mitochondrial outer membrane. Previously, we explained the Warburg type metabolism as a result of the electrical suppression of mitochondria due to the closure of free VDACs that are not bound to HK. Here, we propose a possible new mechanism of high-dose vitamin C (ascorbate) anticancer activity estimated with a simplified computational model. According to the proposed hypothesis and the model, ascorbate oxidation in mitochondria leads to the generation of the negative outer membrane potential (OMP) of opposite sign to the positive OMP generated by the VDAC-HK complexes in cancer cells. The model demonstrates that negative OMP generated by any mechanism, even of relatively low magnitudes, leads to
the reopening of the electrically closed VDACs, thus reprogramming cell energy metabolism.According to the hypothesis, redox mediators, which increase the rate of ascorbate oxidation in mitochondria, should synergistically increase anticancer effects of high-dose ascorbate in accordance with experimental data recorded in the literature. The model shows that even small changes in the VDAC-voltage sensitivity and/or quantity of the VDAC-HK complexes, known to be caused by various physiological factors, might strongly influence the proposed mitochondrial mechanism of ascorbate anticancer activity.
Keywords
References
Abramczyk, H., Surmacki, J.M., Brozek-Pluska, B., Kopec, M. (2021). Revision of commonly accepted Warburg mechanism of cancer development: redox-sensitive mitochondrial cytochromes in breast and brain cancers by Raman imaging. Cancers (Basel). 13 (11): 2599. Doi:10.3390/cancers13112599
Bakalova, R., Zhelev, Z., Miller, T., Aoki, I., Higashi, T. (2020). Vitamin C versus cancer: Ascorbic acid radical and impairment of mitochondrial respiration? Oxid. Med. Cell. Longev. 2020:1504048. Doi: 10.1155/2020/1504048
Bazzan, A.J., Zabrecky, G., Wintering, N., Newberg, A.B., Monti, D.A. (2018). Retrospective evaluation of clinical experience with intravenous ascorbic acid in patients with cancer.Integr. Cancer Ther. 17 (3): 912-920. Doi: 10.1177/1534735418775809
Bernardi, P. (2013). The mitochondrial permeability transition pore: a mystery solved? Front.Physiol. 4: 95. Doi: 10.3389/fphys.2013.00095
Blaszczak, W., Barczak, W., Masternak, J., Kopczyński, P., Zhitkovich, A., Rubiś, B. (2019).Vitamin C as a modulator of the response to cancer therapy. Molecules. 24 (3): 453. Doi:10.3390/molecules24030453
Camara, A.K.S., Zhou, Y., Wen, P.C., Tajkhorshid, E., Kwok, W.M. (2017). Mitochondrial VDAC1: a key gatekeeper as potential therapeutic target. Front. Physiol. 8: 460. Doi: 10.3389/fphys.2017.00460
Cameron, E. & Pauling, L. (1976). Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. U.S.A. 73:3685–3689. Doi: 10.1073/pnas.73.10.3685
Cameron, E. & Pauling, L. (1978). Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. U.S.A. 75: 4538-4542. Doi: 10.1073/pnas.75.9.4538
Carosio, R., Zuccari, G., Orienti, I., Mangraviti, S., Montaldo, P.G. (2007). Sodium ascorbate induces apoptosis in neuroblastoma cell lines by interfering with iron uptake. Mol. Cancer. 6:55. Doi: 10.1186/1476-4598-6-55
Chen, Q., Espey, M. G., Sun, A. Y., Pooput, C., Kirk, K. L., Krishna, M. C., Khosh, D. B., Drisko J., Levine, M. (2008). Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. U.S.A. 105: 11105-11109. Doi: 10.1073/pnas.0804226105
Ciscato, F., Filadi, R., Masgras, I., Pizzi, M., Marin, O., Damiano, N., Pizzo, P., Gori, A., Frezzato, F., Chiara, F., Trentin, L., Bernardi, P., Rasola A. (2020). Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca(2+)-dependent death of cancer cells. EMBO Rep. 21 (7): e49117, Doi: 10.15252/embr.201949117
Colombini, M. (2016). The VDAC channel: Molecular basis for selectivity. Biochim. Biophys. Acta. 1863 (10): 2498-2502. Doi: 10.1016/j.bbamcr.2016.01.019
De Pinto, V., Reina, S., Gupta, A., Messina, A., Mahalakshmi, R. (2016). Role of cysteines in mammalian VDAC isoforms’ function. Biochim. Biophys. Acta. 1857 (8): 1219-1227. Doi:10.1016/j.bbabio.2016.02.020
Feichtinger, R.G., Weis, S., Mayr, J.A., Zimmermann, F., Geilberger, R., Sperl, W., Kofler, B.(2014). Alterations of oxidative phosphorylation complexes in astrocytomas. Glia. 62: 514-525. Doi. 10.1002/glia.22621
Fulda, S. (2009). Tumor resistance to apoptosis. Int. J. Cancer. 124: 511-515. Doi: 10.1002/ijc.24064
Galluzzi, L., Kepp, O., Tajeddine, N., Kroemer, G. (2008). Disruption of the hexokinase-VDAC complex for tumor therapy. Oncogene. 27: 4633-4635. Doi: 10.1038/onc.2008.114
Giansanti, M., Karimi, T., Faraoni, I., Graziani, G. (2021). High-dose vitamin C: Preclinical evidence for tailoring treatment in cancer patients. Cancers (Basel). 13 (6): 1428. Doi:10.3390/cancers13061428
Gilloteaux, J., Jamison, J.M., Arnold, D., Neal, D.R., Summers, J.L. (2006). Morphology and DNA degeneration during autoschizic cell death in bladder carcinoma T24 cells induced by ascorbate and menadione treatment. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 288 (1): 58-83. Doi: 10.1002/ar.a.20276
Gogvadze, V., Orrenius, S., Zhivotovsky, B. (2008). Mitochondria in cancer cells: what is so special about them? Trends in Cell Biol. 18 (4): 165-173. Doi: 10.1016/j.tcb.2008.01.006
González, M.J., Rosario-Pérez, G., Guzmán, A.M., Miranda-Massari, J.R., Duconge, J., Lavergne, J., Fernandez, N., Ortiz, N., Quintero, A., Mikirova, N., Riordan, N.H., Ricart, C.M. (2010). Mitochondria, energy and cancer: The relationship with ascorbic acid. J. Orthomol. Med. 25 (1): 29-38.
Gonzalez, M.J., Miranda Massari, J.R., Duconge, J., Riordan, N.H., Ichim, T., Quintero-Del-Rio, A.I., Ortiz, N. (2012). The bio-energetic theory of carcinogenesis. Med. Hypotheses. 79 (4): 433-439. Doi: 10.1016/j.mehy.2012.06.015
Grimm, S. & Brdiczka, D. (2007). The permeability transition pore in cell death. Apoptosis. 12 (5):841-855. Doi: 10.1007/s10495-007-0747-3
Han, D., Antunes, F., Canali, R., Rettori, D., Cadenas, E. (2003). Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J. Biol. Chem. 278 (8): 5557-5563. Doi: 10.1074/jbc.M210269200
Hill, B.C. & Nicholls, P. (1980). Reduction and activity of cytochrome c in the cytochrome ccytochrome aa3 complex. Biochem. J. 187 (3): 809-818. Doi: 10.1042/bj1870809
Hua, A.B., Justiniano, R., Perer, J., Park, S.L., Li, H., Cabello, C.M., Wondrak, G.T. (2019).Repurposing the electron transfer reactant phenazine methosulfate (PMS) for the apoptotic elimination of malignant melanoma cells through induction of lethal oxidative and mitochondriotoxic stress. Cancers (Basel). 11 (5): 590. Doi: 10.3390/cancers11050590
Kang, J.S., Cho, D., Kim, Y.I., Hahm, E., Yang, Y., Kim, D., Hur, D., Park, H., Bang, S., Hwang,Y.I., Lee, W.J. (2003). L-ascorbic acid (vitamin C) induces the apoptosis of B16 murine melanoma cells via a caspase-8-independent pathway. Cancer Immunol. Immunother. 52 (11): 693-698. Doi: 10.1007/s00262-003-0407-6
Lee, A.C., Xu, X., Colombini, M. (1996). The role of pyridine dinucleotides in regulating the permeability of the mitochondrial outer membrane. J. Biol. Chem. 271 (43): 26724-26731.Doi: 10.1074/jbc.271.43.26724
Lehninger, A.L., UL Hassan, M., Sudduth, H.C. (1954). Phosphorylation coupled to the oxidation of ascorbate by isolated mitochondria. J. Biol. Chem. 210 (2): 911-922. Doi: 10.1016/S0021-9258(18)65418-3
Lemeshko, V.V. (2002). Model of the outer membrane potential generation by the inner membrane of mitochondria. Biophys. J. 82: 684-692. Doi: 10.1016/S0006-3495(02)75431-3
Lemeshko, V.V., Haridas, V., Quijano-Pérez, J.C., Gutterman, J.U. (2006). Avicins, natural anticancer saponins, permeabilize mitochondrial membranes. Arch. Biochem. Biophys. 454:114-122. Doi: 10.1016/j.abb.2006.08.008
Lemeshko, V.V. (2014). VDAC electronics: 1. VDAC-hexo(gluco)kinase generator of the mitochondrial outer membrane potential. Biochim. Biophys. Acta. 1838: 1362-1371. Doi:10.1016/j.bbamem.2014.01.001
Lemeshko, V. (2015). The Warburg effect as a VDAC-hexokinase-mediated electrical suppression of mitochondrial energy metabolism. FASEB J. 29 (Suppl. 1): 725.27.
Lemeshko, V.V. (2017). The mitochondrial outer membrane potential as an electrical feedback control of cell energy metabolism. In: T.K. Rostovtseva (Ed.), Molecular Basis for Mitochondrial Signaling. Springer International Publishing, New York, pp. 217-250. Chapter 9.
Lemeshko, V. (2018). The role of the mitochondrial outer membrane in the control of cell energy metabolism. Rev. Acad. Colomb. Cienc. Exact. Fis. Nat. 42 (162): 6-21 (Spanish). Doi:10.18257/raccefyn.549
Lemeshko, V.V. (2021). Electrical control of the cell energy metabolism at the level of mitochondrial outer membrane. BBA – Biomembranes. 1863: 183493. Doi: 10.1016/j.bbamem.2020.183493
Lv, H., Wang, C., Fang, T., Li, T., Lv, G., Han, Q., Yang, W., Wang, H. (2018). Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2. NPJ Precis.Oncol. 2 (1): 1. Doi: 10.1038/s41698-017-0044-8
Ma, E., Chen, P., Wilkins, H.M., Wang, T., Swerdlow, R.H., Chen, Q. (2017). Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis. Free Radic. Biol. Med. 113: 36-47. Doi: 10.1016/j.freeradbiomed.2017.09.008
Magrì, A., Reina, S., De Pinto, V. (2018). VDAC1 as pharmacological target in cancer and neurodegeneration: focus on its role in apoptosis. Front. Chem. 6: 108. Doi: 10.3389/fchem.2018.00108
Maldonado, E.N., Sheldon, K.L., DeHart, D.N., Patnaik, J., Manevich, Y., Townsend, D. M.,Bezrukov, S.M., Rostovtseva, T.K., Lemasters, J.J. (2013). Voltage-dependent anion channels modulate mitochondria metabolism in cancer cells: regulation by free tubulin and erastin. J. Biol. Chem. 288 (17): 11920-11929. Doi: 10.1074/jbc.M112.433847
Marín-Hernández, A., Rodríguez-Enríquez, S., Vital-González, P.A., Flores-Rodríguez, F.L., Macías-Silva, M., Sosa-Garrocho, M., Moreno-Sánchez, R. (2006). Determining and understanding the control of glycolysis in fast-growth tumor cells. Flux control by an over-expressed but strongly product-inhibited hexokinase. FEBS J. 273: 1975-1988. Doi:10.1111/j.1742-4658.2006.05214.x
McCormick, W.J. (1954). Cancer: the preconditioning factor in pathogenesis; a new etiologic approach. Arch. Pediatr. 71: 313-322.
McCormick, W.J. (1959). Cancer: a collagen disease, secondary to a nutritional deficiency. Arch.Pediatr. 76 (4): 166-171.
Nakashima, R.A., Paggi, M.G., Scott, L.J., Pedersen, P.L. (1988). Purification and characterization of a bindable form of mitochondrial bound hexokinase from the highly glycolytic AS-30D rat hepatoma cell line. Cancer Res. 48: 913-919.
Ngo, B., van Riper, J., Cantley, L.C., Yun, J. (2019). Targeting cancer vulnerabilities with highdose vitamin C. Nature Reviews Cancer. 19 (5): 271-282. Doi: 10.1038/s41568-019-0135-7
Nicholls, P., Hildebrandt, V., Hill, B.C., Nicholls, F., Wrigglesworth, J.M. (1980). Pathways of cytochrome c oxidation by soluble and membrane-bound cytochrome aa3. Can. J. Biochem.58: 969-977. Doi: 10.1139/o80-132
Noto, V., Taper, H.S., Jiang, Y.H., Janssens, J., Bonte, J., De Loecker, W. (1989). 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. 63 (5): 901-906. Doi: 10.1002/1097-0142(19890301)63:5<901::aid-cncr2820630518>3.0.co;2-g
Park, S. (2013). The effects of high concentrations of vitamin C on cancer cells. Nutrients. 5 (9):3496-3505. Doi: 10.3390/nu5093496
Polireddy, K., Dong, R., Reed, G., Yu, J., Chen, P., Williamson, S., Violet, P.C., Pessetto, Z., Godwin, A.K., Fan, F., Levine, M., Drisko, J.A., Chen, Q. (2017). High dose parenteral ascorbate inhibited pancreatic cancer growth and metastasis: Mechanisms and a phase I/IIa study. Sci. Rep. 7 (1): 17188. Doi: 10.1038/s41598-017-17568-8
Roa, F.J., Peña, E., Gatica, M., Escobar-Acuña, K., Saavedra, P., Maldonado, M., Cuevas, M.E., Moraga-Cid, G., Rivas, C.I., Muñoz-Montesino, C. (2020). Therapeutic use of vitamin C in cancer: Physiological considerations. Front. Pharmacol. 11: 211. Doi: 10.3389/fphar.2020.00211
Rostovtseva, T. & Colombini, M. (1997). VDAC channels mediate and gate the flow of ATP:implications for the regulation of mitochondrial function. Biophys. J. 72 (5): 1954-1962. Doi: 10.1016/S0006-3495(97)78841-6
Rostovtseva, T.K., Queralt-Martín, M., Rosencrans, W.M., Bezrukov, S.M. (2020). Targeting the multiple physiologic roles of VDAC with steroids and hydrophobic drugs. Front. Physiol. 11:446. Doi: 10.3389/fphys.2020.00446
Rostovtseva, T.K., Bezrukov, S.M., Hoogerheide, D.P. (2021). Regulation of Mitochondrial Respiration by VDAC Is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains. Int. J. Mol. Sci. 22 (14): 7358. Doi: 10.3390/ijms22147358
Sanadi, D.R. (1964). On the mechanism of oxidative phosphorylation IX. Energy-dependent reduction of nicotinamide adenine dinucleotide by ascorbate and ubiquinone. Biochim.Biophys. Acta. 89: 367-369. Doi: 10.1016/0926-6569(64)90231-7
Semkova, S., Zhelev, Z., Miller, T., Sugaya, K., Aoki, I., Higashi, T., Bakalova, R. (2020).Menadione/Ascorbate induces overproduction of mitochondrial superoxide and impairs mitochondrial function in cancer: comparative study on cancer and normal cells of the same origin. Anticancer Res. 40 (4): 1963-1972. Doi: 10.21873/anticanres.14151
Shteinfer-Kuzmine, A., Amsalem, Z., Arif, T., Zooravlov, A., Shoshan-Barmatz, V. (2018).Selective induction of cancer cell death by VDAC1-based peptides and their potential use in cancer therapy. Mol. Oncol. 12 (7): 1077-1103. Doi: 10.1002/1878-0261.12313
Sun, L., Shukair, S., Naik, T.J., Moazed, F., Ardehali, H. (2008). Glucose phosphorylation and mitochondrial binding are required for the protective effects of hexokinases I and II. Mol.Cell. Biol. 28 (3): 1007-1017. Doi: 10.1128/MCB.00224-07
Tan, W. & Colombini, M. (2007). VDAC closure increases calcium ion flux. Biochim. Biophys.Acta. 1768 (10): 2510-2515. Doi: 10.1016/j.bbamem.2007.06.002
Thayer, W.S. & Rubin, E. (1981). Molecular alterations in the respiratory chain of rat liver after chronic ethanol consumption. J. Biol. Chem. 256 (12): 6090-6097.
Tomasetti, M., Santarelli, L., Alleva, R., Dong, L.-F., Neuzil, J. (2015). Redox-active and redoxsilent compounds: synergistic therapeutics in cancer. Curr. Med. Chem. 22 (5): 552-568. Doi:10.2174/0929867321666140915142219
Valenti, D., de Bari, L., De Filippis, B., Ricceri, L., Vacca, R.A. (2014). Preservation of mitochondrial functional integrity in mitochondria isolated from small cryopreserved mouse brain areas. Anal. Biochem. 444: 25-31. Doi: 10.1016/j.ab.2013.08.030
Van Gorkom, G.N.Y., Lookermans, E.L., van Elssen, C.H.M.J., Bos, G.M.J. (2019). The effect of vitamin C (ascorbic acid) in the treatment of patients with cancer: A systematic review. Nutrients 11 (5): 977. Doi: 10.3390/nu11050977
Verrax, J., Stockis, J., Tison, A., Taper, H.S., Calderon, P.B. (2006). Oxidative stress by ascorbate/menadione association kills K562 human chronic myelogenous leukaemia cells and inhibits its tumour growth in nude mice. Biochem. Pharmacol. 72 (6): 671-680. Doi: 10.1016/j.bcp.2006.05.025
Xia, J., Xu, H., Zhang, X., Allamargot, C., Coleman, K.L., Nessler, R., Frech, I., Tricot, G., Zhan, F. (2017). Multiple myeloma tumor cells are selectively killed by pharmacologicallydosed ascorbic acid. EBioMedicine 18: 41-49. Doi: 10.1016/j.ebiom.2017.02.011
Yonetani, T. (1960). Studies on cytochrome oxidase. II. Steady state properties. J. Biol. Chem. 235(11): 3138-3143.
Zasowska-Nowak, A., Nowak, P.J., Ciałkowska-Rysz, A. (2021). High-dose vitamin C in advanced-stage cancer patients. Nutrients. 13 (3): 735. Doi: 10.3390/nu13030735
Zhou, J., Chen, C., Chen, X., Fei, Y., Jiang, L., Wang, G. (2020). Vitamin C promotes apoptosis and cell cycle arrest in oral squamous cell carcinoma. Front Oncol. 10: 976. Doi: 10.3389/fonc.2020.00976
![Creative Commons License](http://i.creativecommons.org/l/by-nc-nd/4.0/88x31.png)
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Copyright (c) 2021 Revista de la Academia Colombiana de Ciencias Exactas, Físicas y Naturales