Keywords
chemoprevention
cancer
quinone
cell death
How to Cite
Abstract
Epidemiological and experimental findings suggest that vitamin K (VK), in addition to being essential for blood clotting, also functions as a chemopreventive and/or anticancer agent against various types of cancer. In this regard, VK can inhibit the proliferation and differentiation of cancer cells through effects that regulate directly or indirectly key processes such as cell cycle progression, angiogenesis, survival, senescence, and cell death mediated by apoptosis, among others. This review aims to describe relevant and novel concepts around VK in cancer regulation. It addresses specific mechanisms by which VK carries out its effects and highlights its prooxidant function, and action on cellular pathways, and molecular targets mediating tumor development. Furthermore, the potential use of this vitamin in antineoplastic therapy is discussed to prevent or reduce the progression of this disease and improve the life prognosis of patients.
References
Aljuhani, N., Michail, K., Karapetyan, Z. & Siraki, A. G. (2013). The effect of bicarbonate on menadione-induced redox cycling and cytotoxicity: potential involvement of the carbonate radical. Can. J. Physiol. Pharmacol., 91, 783-790. DOI: 10.1139/cjpp-2012-0254.
An, X., Yu, W., Liu, J., Tang, D., Yang, L. & Chen, X. (2024). Oxidative cell death in cancer: mechanisms and therapeutic opportunities. Cell Death Dis., 15, 556. DOI: 10.1038/s41419-024-06939-5.
Bakalova, R., Semkova, S., Ivanova, D., Zhelev, Z., Miller, T., Takeshima, T., Shibata, S., Lazarova, D., Aoki, I. & Higashi, T. (2020). Selective targeting of cancerous mitochondria and suppression of tumor growth using redox-active treatment adjuvant. Oxid Med. Cell Longev., 2020, 6212935. DOI: 10.1155/2020/6212935.
Brancaccio, M., Mennitti, C., Cesaro, A., Fimiani, F., Vano, M., Gargiulo, B., Caiazza, M., Amodio, F., Coto, I., D’Alicandro, G., Mazzaccara, C., Lombardo, B., Pero, R., Terracciano, D., Limongelli, G., Calabro, P., D’Argenio, V., Frisso, G. & Scudiero, O. (2022). The biological role of vitamins in athletes’ muscle, heart and microbiota. Int. J. Environ. Res. Public Health, 19, 1249. DOI: 10.3390/ijerph19031249.
Caricchio, R., Kovalenko, D., Kaufmann, W. K. & Cohen, P. L. (1999). Apoptosis provoked by the oxidative stress inducer menadione [Vitamin K(3)] is mediated by the Fas/Fas ligand system. Clin. Immunol., 93, 65-74. DOI: 10.1006/clim.1999.4757.
Chang, N. C. (2020). Autophagy and stem cells: self-eating for self-renewal. Front. Cell Dev. Biol., 8, 138. DOI: 10.3389/fcell.2020.00138.
Chen, A., Li, J., Shen, N., Huang, H. & Hang, Q. (2024). Vitamin K: new insights related to senescence and cancer metastasis. Biochim. Biophys. Acta Rev. Cancer, 1879, 189057. DOI: 10.1016/j.bbcan.2023.189057.
Chen, R. & Pignatello, J. (1997). Role of quinone intermediates as electron shuttles in Fenton and photoassisted Fenton oxidations of aromatic compounds. Environ. Sci. Technol., 31, 2399-2406.
Dasari, S., Ali, S. M., Zheng, G., Chen, A., Dontaraju, V. S., Bosland, M. C., Kajdacsy-Balla, A. & Munirathinam, G. (2017). Vitamin K and its analogs: potential avenues for prostate cancer management. Oncotarget, 8, 57782-57799. DOI: 10.18632/oncotarget.17997.
Dasari, S., Samy, A., Kajdacsy-Balla, A., Bosland, M. C. & Munirathinam, G. (2018). Vitamin K2, a menaquinone present in dairy products targets castration-resistant prostate cancer cell-line by activating apoptosis signaling. Food Chem. Toxicol., 115, 218-227. DOI: 10.1016/j.fct.2018.02.018.
Debnath, J., Gammoh, N. & Ryan, K. M. (2023). Autophagy and autophagy-related pathways in cancer. Nat. Rev. Mol. Cell Biol., 24, 560-575. DOI: 10.1038/s41580-023-00585-z.
Duan, F., Mei, C., Yang, L., Zheng, J., Lu, H., Xia, Y., Hsu, S., Liang, H. & Hong, L. (2020). Vitamin K2 promotes PI3K/AKT/HIF-1alpha-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells. Sci. Rep., 10, 7714. DOI: 10.1038/s41598-020-64880-x.
Edinger, A. L. & Thompson, C. B. (2004). Death by design: apoptosis, necrosis and autophagy. Curr. Opin. Cell Biol., 16, 663-669. DOI: 10.1016/j.ceb.2004.09.011.
Elmore, S. (2007). Apoptosis: a review of programmed cell death. Toxicol. Pathol., 35, 495-516. DOI: 10.1080/01926230701320337.
Gilloteaux, J., Jamison, J. M., Arnold, D. & Summers, J. L. (2001). Autoschizis: another cell death for cancer cells induced by oxidative stress. Ital. J. Anat. Embryol., 106, 79-92.
Gilloteaux, J., Jamison, J. M. & Summers, J. L. (2014). Pro-oxidant treatment of human prostate carcinoma (DU145) induces autoschizis cell death: autophagosomes build up out of injured endomembranes and mitochondria. Ultrastruct. Pathol., 38, 315-328. DOI: 10.3109/01913123.2014.927404.
Guizzardi, S., Picotto, G., Rodriguez, V., Welsh, J., Narvaez, C., Bohl, L. & Tolosa de Talamoni, N. (2020). Combined treatment of menadione and calcitriol increases the antiproliferative effect by promoting oxidative/nitrosative stress, mitochondrial dysfunction, and autophagy in breast cancer MCF-7 cells. Can. J. Physiol. Pharmacol., 98, 548-556. DOI: 10.1139/cjpp-2019-0585.
Gul, S., Maqbool, M. F., Maryam, A., Khan, M., Shakir, H. A., Irfan, M., Ara, C., Li, Y. & Ma, T. (2022). Vitamin K: a novel cancer chemosensitizer. Biotechnol. Appl. Biochem., 69, 2641-2657. DOI: 10.1002/bab.2312.
Halder, M., Petsophonsakul, P., Akbulut, A. C., Pavlic, A., Bohan, F., Anderson, E., Maresz, K., Kramann, R. & Schurgers, L. (2019). Vitamin K: double bonds beyond coagulation insights into differences between vitamin K1 and K2 in health and disease. Int. J. Mol. Sci., 20, 896. DOI: 10.3390/ijms20040896.
Hanahan, D. & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144, 646-674. DOI: 10.1016/j.cell.2011.02.013.
Ivanova, D., Zhelev, Z., Getsov, P., Nikolova, B., Aoki, I., Higashi, T. & Bakalova, R. (2018). Vitamin K: redox-modulation, prevention of mitochondrial dysfunction and anticancer effect. Redox Biol., 16, 352-358. DOI: 10.1016/j.redox.2018.03.013.
Jamison, J. M., Gilloteaux, J., Taper, H. S., Calderon, P. B. & Summers, J. L. (2002). Autoschizis: a novel cell death. Biochem. Pharmacol., 63, 1773-1783. DOI: 10.1016/s0006-2952(02)00904-8.
Kazmierczak-Baranska, J. & Karwowski, B. T. (2022). Vitamin K contribution to DNA damage-advantage or disadvantage? A human health response. Nutrients, 14, 4219. DOI: 10.3390/nu14204219.
Kim, Y. J., Shin, Y. K., Sohn, D. S. & Lee, C. S. (2014). Menadione induces the formation of reactive oxygen species and depletion of GSH-mediated apoptosis and inhibits the FAK-mediated cell invasion. Naunyn-Schmiedeberg’s archives of pharmacology, 387, 799-809. DOI: 10.1007/s00210-014-0997-x.
Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo-San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., Choi, M. E., Chu, C. T., Codogno, P., Colombo, M. I., Cuervo, A. M., Deretic, V., Dikic, I., Elazar, Z., Eskelinen, E. L., Fimia, G. M., Gewirtz, D. A., Green, D. R., Hansen, M., Jaattela, M., Johansen, T., Juhasz, G., Karantza, V., Kraft, C., Kroemer, G., Ktistakis, N. T., Kumar, S., Lopez-Otin, C., Macleod, K. F., Madeo, F., Martinez, J., Melendez, A., Mizushima, N., Munz, C., Penninger, J. M., Perera, R. M., Piacentini, M., Reggiori, F., Rubinsztein, D. C., Ryan, K. M., Sadoshima, J., Santambrogio, L., Scorrano, L., Simon, H. U., Simon, A. K., Simonsen, A., Stolz, A., Tavernarakis, N., Tooze, S. A., Yoshimori, T., Yuan, J., Yue, Z., Zhong, Q., Galluzzi, L. & Pietrocola, F. (2021). Autophagy in major human diseases. EMBO. J., 40, e108863. DOI: 10.15252/embj.2021108863.
Kocaturk, N. M., Akkoc, Y., Kig, C., Bayraktar, O., Gozuacik, D. & Kutlu, O. (2019). Autophagy as a molecular target for cancer treatment. Eur. J. Pharm. Sci., 134, 116-137. DOI: 10.1016/j.ejps.2019.04.011.
Lamson, D. W. & Plaza, S. M. (2003). The anticancer effects of vitamin K. Altern. Med. Rev., 8, 303-318.
Lee, M. H., Cho, Y., Kim, D. H., Woo, H. J., Yang, J. Y., Kwon, H. J., Yeon, M. J., Park, M., Kim, S. H., Moon, C., Tharmalingam, N., Kim, T. U. & Kim, J. B. (2016). Menadione induces G2/M arrest in gastric cancer cells by down-regulation of CDC25C and proteasome mediated degradation of CDK1 and cyclin B1. Am. J. Transl. Res., 8, 5246-5255.
Li, X., He, S. & Ma, B. (2020). Autophagy and autophagy-related proteins in cancer. Mol. Cancer, 19, 12. DOI: 10.1186/s12943-020-1138-4.
Li, Y., Chen, J. P., Duan, L. & Li, S. (2018). Effect of vitamin K2 on type 2 diabetes mellitus: A review. Diabetes Res. Clin. Pract., 136, 39-51. DOI: 10.1016/j.diabres.2017.11.020.
Linowiecka, K., Foksinski, M. & Brozyna, A. A. (2020). Vitamin C Transporters and their implications in carcinogenesis. Nutrients, 12, 3869. DOI: 10.3390/nu12123869.
Lu, X., Kong, L., Wang, X., Liu, W., Ma, P. & Jiang, L. (2019). 17beta‑hydroxysteroid dehydrogenase 4 induces liver cancer proliferation‑associated genes via STAT3 activation. Oncol. Rep., 41, 2009-2019. DOI: 10.3892/or.2019.6981.
Lu, X., Ma, P., Kong, L., Wang, X., Wang, Y. & Jiang, L. (2021). Vitamin K2 inhibits hepatocellular carcinoma cell proliferation by binding to 17beta-Hydroxysteroid dehydrogenase 4. Front. Oncol., 11, 757603. DOI: 10.3389/fonc.2021.757603.
Lu, X., Ma, P., Shi, Y., Yao, M., Hou, L., Zhang, P. & Jiang, L. (2015). NF-kappaB increased expression of 17beta-hydroxysteroid dehydrogenase 4 promotes HepG2 proliferation via inactivating estradiol. Mol. Cell. Endocrinol., 401, 1-11. DOI: 10.1016/j.mce.2014.11.016.
Marchionatti, A. M., Picotto, G., Narvaez, C. J., Welsh, J. & Tolosa de Talamoni, N. G. (2009). Antiproliferative action of menadione and 1,25(OH)2D3 on breast cancer cells. J. Steroid. Biochem. Mol. Biol., 113, 227-232. DOI: 10.1016/j.jsbmb.2009.01.004.
Matsushita, M., Fujita, K. & Nonomura, N. (2020). Influence of diet and nutrition on prostate cancer. Int. J. Mol. Sci., 21, 1447. DOI: 10.3390/ijms21041447.
Miyazawa, K., Yaguchi, M., Funato, K., Gotoh, A., Kawanishi, Y., Nishizawa, Y., Yuo, A. & Ohyashiki, K. (2001). Apoptosis/differentiation-inducing effects of vitamin K2 on HL-60 cells: dichotomous nature of vitamin K2 in leukemia cells. Leukemia, 15, 1111-1117. DOI: 10.1038/sj.leu.2402155.
Mladenka, P., Macakova, K., Kujovska Krcmova, L., Javorska, L., Mrstna, K., Carazo, A., Protti, M., Remiao, F. & Novakova, L. (2022). Vitamin K - sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity. Nutr. Rev., 80, 677-698. DOI: 10.1093/nutrit/nuab061.
Nakamura, H. & Takada, K. (2021). Reactive oxygen species in cancer: current findings and future directions. Cancer Sci., 112, 3945-3952. DOI: 10.1111/cas.15068.
Nutter, L. M., Ngo, E. O., Fisher, G. R. & Gutierrez, P. L. (1992). DNA strand scission and free radical production in menadione-treated cells. Correlation with cytotoxicity and role of NADPH quinone acceptor oxidoreductase. J. Biol. Chem., 267, 2474-2479.
Perillo, B., Di Donato, M., Pezone, A., Di Zazzo, E., Giovannelli, P., Galasso, G., Castoria, G. & Migliaccio, A. (2020). ROS in cancer therapy: the bright side of the moon. Exp. Mol. Med., 52, 192-203. DOI: 10.1038/s12276-020-0384-2.
Pervaiz, S. & Clement, M. V. (2007). Superoxide anion: oncogenic reactive oxygen species? Int. J. Biochem. Cell. Biol., 39, 1297-1304. DOI: 10.1016/j.biocel.2007.04.007.
Samykutty, A., Shetty, A. V., Dakshinamoorthy, G., Kalyanasundaram, R., Zheng, G., Chen, A., Bosland, M. C., Kajdacsy-Balla, A. & Gnanasekar, M. (2013). Vitamin k2, a naturally occurring menaquinone, exerts therapeutic effects on both hormone-dependent and hormone-independent prostate cancer cells. Evid. Based Complement. Alternat. Med., 2013, 287358. DOI: 10.1155/2013/287358.
Segovia-Mendoza, M., Garcia-Quiroz, J., Diaz, L. & Garcia-Becerra, R. (2021). Combinations of calcitriol with anticancer treatments for breast cancer: an update. Int. J. Mol. Sci., 22, 12741. DOI: 10.3390/ijms222312741.
Shetty, A., Dasari, S., Banerjee, S., Gheewala, T., Zheng, G., Chen, A., Kajdacsy-Balla, A., Bosland, M. C. & Munirathinam, G. (2016). Hepatoma-derived growth factor: a survival-related protein in prostate oncogenesis and a potential target for vitamin K2. Urol. Oncol., 34, 483 e481-483 e488. DOI: 10.1016/j.urolonc.2016.05.027.
Simes, D. C., Viegas, C. S. B., Araujo, N. & Marreiros, C. (2020). Vitamin K as a diet supplement with impact in human health: current evidence in age-related diseases. Nutrients, 12, 138. DOI: 10.3390/nu12010138.
Swamynathan, M. M., Kuang, S., Watrud, K. E., Doherty, M. R., Gineste, C., Mathew, G., Gong, G. Q., Cox, H., Cheng, E., Reiss, D., Kendall, J., Ghosh, D., Reczek, C. R., Zhao, X., Herzka, T., Spokaite, S., Dessus, A. N., Kim, S. T., Klingbeil, O., Liu, J., Nowak, D. G., Alsudani, H., Wee, T. L., Park, Y., Minicozzi, F., Rivera, K., Almeida, A. S., Chang, K., Chakrabarty, R. P., Wilkinson, J. E., Gimotty, P. A., Diermeier, S. D., Egeblad, M., Vakoc, C. R., Locasale, J. W., Chandel, N. S., Janowitz, T., Hicks, J. B., Wigler, M., Pappin, D. J., Williams, R. L., Cifani, P., Tuveson, D. A., Laporte, J. & Trotman, L. C. (2024). Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function. Science, 386, eadk9167. DOI: 10.1126/science.adk9167.
Thijssen, H. H., Vervoort, L. M., Schurgers, L. J. & Shearer, M. J. (2006). Menadione is a metabolite of oral vitamin K. Br. J. Nutr., 95, 260-266. DOI: 10.1079/bjn20051630.
Tokita, H., Tsuchida, A., Miyazawa, K., Ohyashiki, K., Katayanagi, S., Sudo, H., Enomoto, M., Takagi, Y. & Aoki, T. (2006). Vitamin K2-induced antitumor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines. Int. J. Mol. Med., 17, 235-243.
Venturelli, S., Leischner, C., Helling, T., Burkard, M. & Marongiu, L. (2021). Vitamins as possible cancer biomarkers: significance and limitations. Nutrients, 13, 3914. DOI: 10.3390/nu13113914.
Wang, Z., Wang, M., Finn, F. & Carr, B. I. (1995). The growth inhibitory effects of vitamins K and their actions on gene expression. Hepatology, 22, 876-882.
Welsh, J., Bak, M. J. & Narvaez, C. J. (2022). New insights into vitamin K biology with relevance to cancer. Trends Mol. Med., 28, 864-881. DOI: 10.1016/j.molmed.2022.07.002.
Wu, F. Y. & Sun, T. P. (1999). Vitamin K3 induces cell cycle arrest and cell death by inhibiting Cdc25 phosphatase. Eur. J. Cancer, 35, 1388-1393. doi: 10.1016/s0959-8049(99)00156-2.
Yamamoto, T., Nakamura, H., Liu, W., Cao, K., Yoshikawa, S., Enomoto, H., Iwata, Y., Koh, N., Saito, M., Imanishi, H., Shimomura, S., Iijima, H., Hada, T. & Nishiguchi, S. (2009). Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K(2). J. Gastroenterol., 44, 228-235. DOI: 10.1007/s00535-008-2304-4.
Yokoyama, T., Miyazawa, K., Naito, M., Toyotake, J., Tauchi, T., Itoh, M., Yuo, A., Hayashi, Y., Georgescu, M. M., Kondo, Y., Kondo, S. & Ohyashiki, K. (2008). Vitamin K2 induces autophagy and apoptosis simultaneously in leukemia cells. Autophagy, 4, 629-640. DOI: 10.4161/auto.5941.
Yokoyama, T., Miyazawa, K., Yoshida, T. & Ohyashiki, K. (2005). Combination of vitamin K2 plus imatinib mesylate enhances induction of apoptosis in small cell lung cancer cell lines. Int. J. Oncol., 26, 33-40.
Yun, C. W. & Lee, S. H. (2018). The roles of autophagy in cancer. Int. J. Mol. Sci., 19, 3466. DOI: 10.3390/ijms19113466.
Zhang, Y., Zhang, B., Zhang, A., Zhao, Y., Zhao, J., Liu, J., Gao, J., Frang, D. & Rao, Z. (2012). Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells. Clinics (Sao Paulo), 67, 1093-1099. DOI: 10.6061/clinics/2012(09)18.
TIP Magazine Specialized in Chemical-Biological Sciences, distributed under Creative Commons License: Attribution + Noncommercial + NoDerivatives 4.0 International.