Vitamin C as an Anticancer Agent: Regulation of Signaling Pathways

Author(s): Ghazala Butt, Ammad A. Farooqi*, Aima Adylova, Rukset Attar, Seher Yilmaz, Konysbayeva K. Konysbayevna, Uteuliyev Y. Sabitaliyevich, Maria L. Gasparri, Baojun Xu*

Journal Name: Current Topics in Medicinal Chemistry

Volume 20 , Issue 21 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Treatment options for effective treatment of cancer with minimum off-target effects and maximum clinical outcomes have remained overarching goals in the clinical oncology. Vitamin C has remained in the shadows of controversy since the past few decades; burgeoning evidence has started to shed light on wide-ranging anticancer effects exerted by Vitamin C to induce apoptosis in drug-resistant cancer cells, inhibit uncontrolled proliferation of the cancer cells and metastatic spread. Landmark achievements in molecular oncology have ushered in a new era, and researchers have focused on the identification of oncogenic pathways regulated by Vitamin C in different cancers. However, there are visible knowledge gaps in our understanding related to the ability of Vitamin C to modulate a myriad of transduction cascades. There are scattered pieces of scientific evidence about promising potential of Vitamin C to regulate JAK-STAT, TGF/SMAD, TRAIL and microRNAs in different cancers. However, published data is insufficient and needs to be investigated comprehensively to enable basic and clinical researchers to reap full benefits and promote result-oriented transition of Vitamin C into various phases of clinical trials. In this review, we will emphasize on available evidence related to the regulation of oncogenic cell signaling pathways by Vitamin C in different cancers. We will also highlight the conceptual gaps, which need detailed and cutting-edge research.

Keywords: Vitamin C, Anticancer, Signaling pathways, Protein network, Clinical trials, Clinical oncology.

Cameron, E.; Campbell, A. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem. Biol. Interact., 1974, 9(4), 285-315.
[] [PMID: 4430016]
Cameron, E.; Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. USA, 1976, 73(10), 3685-3689.
[] [PMID: 1068480]
Cameron, E.; Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. USA, 1978, 75(9), 4538-4542.
[] [PMID: 279931]
Creagan, E.T.; Moertel, C.G.; O’Fallon, J.R.; Schutt, A.J.; O’Connell, M.J.; Rubin, J.; Frytak, S. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N. Engl. J. Med., 1979, 301(13), 687-690.
[] [PMID: 384241]
Moertel, C.G.; Fleming, T.R.; Creagan, E.T.; Rubin, J.; O’Connell, M.J.; Ames, M.M. 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. N. Engl. J. Med., 1985, 312(3), 137-141.
[] [PMID: 3880867]
Ngo, B.; Van Riper, J.M.; Cantley, L.C.; Yun, J. Targeting cancer vulnerabilities with high-dose vitamin C. Nat. Rev. Cancer, 2019, 19(5), 271-282.
[] [PMID: 30967651]
Blaszczak, W.; Barczak, W.; Masternak, J.; Kopczyński, P.; Zhitkovich, A.; Rubiś, B. Vitamin C as a modulator of the response to cancer therapy. Molecules, 2019, 24(3),E453
[] [PMID: 30695991]
Ang, A.; Pullar, J.M.; Currie, M.J.; Vissers, M.C.M. Vitamin C and immune cell function in inflammation and cancer. Biochem. Soc. Trans., 2018, 46(5), 1147-1159.
[] [PMID: 30301842]
Gerecke, C.; Schumacher, F.; Berndzen, A.; Homann, T.; Kleuser, B. Vitamin C in combination with inhibition of mutant IDH1 synergistically activates TET enzymes and epigenetically modulates gene silencing in colon cancer cells. Epigenetics, 2019, 17, 1-16.
[PMID: 31505989]
Shenoy, N.; Bhagat, T.D.; Cheville, J.; Lohse, C.; Bhattacharyya, S.; Tischer, A.; Machha, V.; Gordon-Mitchell, S.; Choudhary, G.; Wong, L.F.; Gross, L.; Ressigue, E.; Leibovich, B.; Boorjian, S.A.; Steidl, U.; Wu, X.; Pradhan, K.; Gartrell, B.; Agarwal, B.; Pagliaro, L.; Suzuki, M.; Greally, J.M.; Rakheja, D.; Thompson, R.H.; Susztak, K.; Witzig, T.; Zou, Y.; Verma, A. Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma. J. Clin. Invest., 2019, 129(4), 1612-1625.
[] [PMID: 30702441]
Ge, G.; Peng, D.; Xu, Z.; Guan, B.; Xin, Z.; He, Q.; Zhou, Y.; Li, X.; Zhou, L.; Ci, W. Restoration of 5-hydroxymethylcytosine by ascorbate blocks kidney tumour growth. EMBO Rep., 2018, 19(8),e45401
[] [PMID: 29959161]
Wohlrab, C.; Vissers, M.C.M.; Phillips, E.; Morrin, H.; Robinson, B.A.; Dachs, G.U. The association between ascorbate and the hypoxia-inducible factors in human renal cell carcinoma requires a functional von Hippel-Lindau protein. Front. Oncol., 2018, 8(8), 574.
[] [PMID: 30555801]
Wu, X.; Park, M.; Sarbassova, D.A.; Ying, H.; Lee, M.G.; Bhattacharya, R.; Ellis, L.; Peterson, C.B.; Hung, M.C.; Lin, H.K.; Bersimbaev, R.I.; Song, M.S.; Sarbassov, D.D. A chirality-dependent action of vitamin C in suppressing Kirsten rat sarcoma mutant tumor growth by the oxidative combination: Rationale for cancer therapeutics. Int. J. Cancer, 2019, 146(10), 2822-2828.
[] [PMID: 31472018]
Wang, C.; Lv, H.; Yang, W.; Li, T.; Fang, T.; Lv, G.; Han, Q.; Dong, L.; Jiang, T.; Jiang, B.; Yang, G.; Wang, H. SVCT-2 determines the sensitivity to ascorbate-induced cell death in cholangiocarcinoma cell lines and patient derived xenografts. Cancer Lett., 2017, 398(398), 1-11.
[] [PMID: 28385602]
Jung, S.A.; Lee, D.H.; Moon, J.H.; Hong, S.W.; Shin, J.S.; Hwang, I.Y.; Shin, Y.J.; Kim, J.H.; Gong, E.Y.; Kim, S.M.; Lee, E.Y.; Lee, S.; Kim, J.E.; Kim, K.P.; Hong, Y.S.; Lee, J.S.; Jin, D.H.; Kim, T.; Lee, W.J. L-Ascorbic acid can abrogate SVCT-2-dependent cetuximab resistance mediated by mutant KRAS in human colon cancer cells. Free Radic. Biol. Med., 2016, 95, 200-208.
[] [PMID: 27012422]
Lv, H.; Wang, C.; Fang, T.; Li, T.; Lv, G.; Han, Q.; Yang, W.; Wang, H. Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2. NPJ Precis Oncol, 2018, 2(1)
Subramanian, V.S.; Sabui, S.; Marchant, J.S.; Said, H.M. MicroRNA-103a regulates sodium-dependent vitamin C transporter-1 expression in intestinal epithelial cells. J. Nutr. Biochem., 2019, 65, 46-53.
[] [PMID: 30616065]
Cho, S.; Chae, J.S.; Shin, H.; Shin, Y.; Kim, Y.; Kil, E.J.; Byun, H.S.; Cho, S.H.; Park, S.; Lee, S.; Yeom, C.H. Enhanced anticancer effect of adding magnesium to vitamin c therapy: inhibition of hormetic response by SVCT-2 activation. Transl. Oncol., 2020, 13(2), 401-409.
[] [PMID: 31901552]
Pastor, W.A.; Aravind, L.; Rao, A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell Biol., 2013, 14(6), 341-356.
[] [PMID: 23698584]
Xu, Y.P.; Lv, L.; Liu, Y.; Smith, M.D.; Li, W.C.; Tan, X.M.; Cheng, M.; Li, Z.; Bovino, M.; Aubé, J.; Xiong, Y. Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy. J. Clin. Invest., 2019, 129(10), 4316-4331.
[] [PMID: 31310587]
Sun, T.T.; Tang, J.Y.; Du, W.; Zhao, H.J.; Zhao, G.; Yang, S.L.; Chen, H.Y.; Hong, J.; Fang, J.Y. Bidirectional regulation between TMEFF2 and STAT3 may contribute to Helicobacter pylori-associated gastric carcinogenesis. Int. J. Cancer, 2015, 136(5), 1053-1064.
[] [PMID: 24996057]
Han, H.; Xu, J.; Ji, W.; Wang, L.; Wang, A. Upregulation of TMEFF2 is involved in the antiproliferative effects of vitamin C and tyrphostin AG490 on GES-1 and AGS cells. Oncol. Lett., 2019, 17(1), 652-659.
[PMID: 30655813]
Shenoy, N.; Bhagat, T.; Nieves, E.; Stenson, M.; Lawson, J.; Choudhary, G.S.; Habermann, T.; Nowakowski, G.; Singh, R.; Wu, X.; Verma, A.; Witzig, T.E. Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. Blood Cancer J., 2017, 7(7), 587.
Zeng, L.H.; Wang, Q.M.; Feng, L.Y.; Ke, Y.D.; Xu, Q.Z.; Wei, A.Y.; Zhang, C.; Ying, R.B. High-dose vitamin C suppresses the invasion and metastasis of breast cancer cells via inhibiting epithelial-mesenchymal transition. OncoTargets Ther., 2019, 12(12), 7405-7413.
[] [PMID: 31571901]
Gan, L.; Camarena, V.; Mustafi, S.; Wang, G. Vitamin C inhibits triple-negative breast cancer metastasis by affecting the expression of YAP1 and synaptopodin 2. Nutrients, 2019, 11(12), 2997.
[] [PMID: 31817810]
Cottini, F.; Hideshima, T.; Xu, C.; Sattler, M.; Dori, M.; Agnelli, L.; ten Hacken, E.; Bertilaccio, M.T.; Antonini, E.; Neri, A.; Ponzoni, M.; Marcatti, M.; Richardson, P.G.; Carrasco, R.; Kimmelman, A.C.; Wong, K.K.; Caligaris-Cappio, F.; Blandino, G.; Kuehl, W.M.; Anderson, K.C.; Tonon, G. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nat. Med., 2014, 20(6), 599-606.
[] [PMID: 24813251]
Warren, C.F.A.; Wong-Brown, M.W.; Bowden, N.A. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis., 2019, 10(3), 177.
[] [PMID: 30792387]
Walensky, L.D. Targeting BAX to drug death directly. Nat. Chem. Biol., 2019, 15(7), 657-665.
[] [PMID: 31209350]
von Karstedt, S.; Montinaro, A.; Walczak, H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Rev. Cancer, 2017, 17(6), 352-366.
[] [PMID: 28536452]
Mane, S.D.; Thoh, M.; Sharma, D.; Sandur, S.K.; Naidu, K.A. Ascorbyl stearate promotes apoptosis through intrinsic mitochondrial pathway in HeLa cancer cells. Anticancer Res., 2016, 36(12), 6409-6417.
[] [PMID: 27919962]
Chen, X.Y.; Chen, Y.; Qu, C.J.; Pan, Z.H.; Qin, Y.; Zhang, X.; Liu, W.J.; Li, D.F.; Zheng, Q. Vitamin C induces human melanoma A375 cell apoptosis via Bax- and Bcl-2-mediated mitochondrial pathways. Oncol. Lett., 2019, 18(4), 3880-3886.
[] [PMID: 31516599]
Perez-Cruz, I.; Cárcamo, J.M.; Golde, D.W. Caspase-8 dependent TRAIL-induced apoptosis in cancer cell lines is inhibited by vitamin C and catalase. Apoptosis, 2007, 12(1), 225-234.
[] [PMID: 17031493]
Sant, D.W.; Mustafi, S.; Gustafson, C.B.; Chen, J.; Slingerland, J.M.; Wang, G. Vitamin C promotes apoptosis in breast cancer cells by increasing TRAIL expression. Sci. Rep., 2018, 8(1), 5306.
[] [PMID: 29593282]
Mustafi, S.; Camarena, V.; Qureshi, R.; Yoon, H.; Volmar, C.H.; Huff, T.C.; Sant, D.W.; Zheng, L.; Brothers, S.P.; Wahlestedt, C.; Slingerland, J.; Wang, G. Vitamin C supplementation expands the therapeutic window of BETi for triple negative breast cancer. EBioMedicine, 2019, 43, 201-210.
[] [PMID: 30975544]
Rojo de la Vega, M.; Chapman, E.; Zhang, D.D. NRF2 and the Hallmarks of Cancer Cancer Cell, 2018, 34(1), 21-43.
Singh, B.; Chatterjee, A.; Ronghe, A.M.; Bhat, N.K.; Bhat, H.K. Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer. BMC Cancer, 2013, 13(13), 253.
[] [PMID: 23697596]
Chatterjee, A.; Ronghe, A.; Singh, B.; Bhat, N.K.; Chen, J.; Bhat, H.K. Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC b-Zip transcription factors in estrogen-induced breast carcinogenesis. J. Biochem. Mol. Toxicol., 2014, 28(12), 529-538.
[] [PMID: 25130429]
Su, X.; Shen, Z.; Yang, Q.; Sui, F.; Pu, J.; Ma, J.; Ma, S.; Yao, D.; Ji, M.; Hou, P. Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms. Theranostics, 2019, 9(15), 4461-4473.
[] [PMID: 31285773]
Bober, P.; Tomková, Z.; Alexovič, M.; Ropovik, I.; Sabo, J. The unfolded protein response controls endoplasmic reticulum stress-induced apoptosis of MCF-7 cells via a high dose of vitamin C treatment. Mol. Biol. Rep., 2019, 46(1), 1275-1284.
[] [PMID: 30694453]
Singh, B.; Ronghe, A.M.; Chatterjee, A.; Bhat, N.K.; Bhat, H.K. MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis. Carcinogenesis, 2013, 34(5), 1165-1172.
[] [PMID: 23492819]
Wang, B.; Teng, Y.; Liu, Q. MicroRNA-153 Regulates NRF2 Expression and is associated with breast carcinogenesis. Clin. Lab., 2016, 62(1-2), 39-47.
[] [PMID: 27012032]
Gao, X.; Wei, K.; Hu, B.; Xu, K.; Tang, B. Ascorbic acid induced HepG2 cells’ apoptosis via intracellular reductive stress. Theranostics, 2019, 9(14), 4233-4240.
[] [PMID: 31281544]
Zhang, X.; Liu, T.; Li, Z.; Feng, Y.; Corpe, C.; Liu, S.; Zhang, J.; He, X.; Liu, F.; Xu, L.; Shen, L.; Li, S.; Xia, Q.; Peng, X.; Zhou, X.; Chen, W.; Zhang, X.; Xu, J.; Wang, J. Hepatomas are exquisitely sensitive to pharmacologic ascorbate (P-AscH-). Theranostics, 2019, 9(26), 8109-8126.
[] [PMID: 31754384]
Zheng, Z.; Luo, G.; Shi, X.; Long, Y.; Shen, W.; Li, Z.; Zhang, X. The Xc- inhibitor sulfasalazine improves the anti-cancer effect of pharmacological vitamin C in prostate cancer cells via a glutathione-dependent mechanism. Cell Oncol. (Dordr.), 2020, 43, 95-106.
[] [PMID: 31617161]
Luchtel, R.A.; Bhagat, T.; Pradhan, K.; Jacobs, W.R., Jr; Levine, M.; Verma, A.; Shenoy, N. High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model. Proc. Natl. Acad. Sci. USA, 2020, 117(3), 1666-1677.
[] [PMID: 31911474]
Padayatty, S.J.; Sun, H.; Wang, Y.; Riordan, H.D.; Hewitt, S.M.; Katz, A.; Wesley, R.A.; Levine, M. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann. Intern. Med., 2004, 140(7), 533-537.
[] [PMID: 15068981]
Gillberg, L.; Ørskov, A.D.; Nasif, A.; Ohtani, H.; Madaj, Z.; Hansen, J.W.; Rapin, N.; Mogensen, J.B.; Liu, M.; Dufva, I.H.; Lykkesfeldt, J.; Hajkova, P.; Jones, P.A.; Grønbæk, K. Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes. Clin. Epigenetics, 2019, 11(1), 143.
[] [PMID: 31623675]
Abdel-Latif, M.M.M.; Babar, M.; Kelleher, D.; Reynolds, J.V. A pilot study of the impact of Vitamin C supplementation with neoadjuvant chemoradiation on regulators of inflammation and carcinogenesis in esophageal cancer patients. J. Cancer Res. Ther., 2019, 15(1), 185-191.
[PMID: 3088077]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [1868 - 1875]
Pages: 8
DOI: 10.2174/1568026620666200710102841
Price: $65

Article Metrics

PDF: 28