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Published in: Journal of Translational Medicine 1/2009

Open Access 01-12-2009 | Research

High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis

Authors: Chang-Hwan Yeom, Gunsup Lee, Jin-Hee Park, Jaelim Yu, Seyeon Park, Sang-Yeop Yi, Hye Ree Lee, Young Seon Hong, Joosung Yang, Sukchan Lee

Published in: Journal of Translational Medicine | Issue 1/2009

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Abstract

To test the carcinostatic effects of ascorbic acid, we challenged the mice of seven experimental groups with 1.7 × 10-4 mol high dose concentration ascorbic acid after intraperitoneal administrating them with sarcoma S-180 cells. The survival rate was increased by 20% in the group that received high dose concentration ascorbic acid, compared to the control. The highest survival rate was observed in the group in which 1.7 × 10-4 mol ascorbic acid had been continuously injected before and after the induction of cancer cells, rather than just after the induction of cancer cells. The expression of three angiogenesis-related genes was inhibited by 0.3 times in bFGF, 7 times in VEGF and 4 times in MMP2 of the groups with higher survival rates. Biopsy Results, gene expression studies, and wound healing analysis in vivo and in vitro suggested that the carcinostatic effect induced by high dose concentration ascorbic acid occurred through inhibition of angiogenesis.
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Literature
1.
go back to reference Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, Ward E, Wu XC, Eheman C, Anderson R: Annual report to the nation on the status of cancer, 1975-2005featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst. 2008, 100: 1672-1694. 10.1093/jnci/djn389.PubMedCentralCrossRefPubMed Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, Ward E, Wu XC, Eheman C, Anderson R: Annual report to the nation on the status of cancer, 1975-2005featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst. 2008, 100: 1672-1694. 10.1093/jnci/djn389.PubMedCentralCrossRefPubMed
2.
go back to reference Gonzalez MJ, Miranda-Massari JR, Mora EM, Guzman A, Riordan NH, Riordan HD, Casciari JJ, Jackson JA, Roman-Franco A: Orthomolecular oncology review: ascorbic acid and cancer 25 years later. Integr Cancer Ther. 2005, 4: 32-44. 10.1177/1534735404273861.CrossRefPubMed Gonzalez MJ, Miranda-Massari JR, Mora EM, Guzman A, Riordan NH, Riordan HD, Casciari JJ, Jackson JA, Roman-Franco A: Orthomolecular oncology review: ascorbic acid and cancer 25 years later. Integr Cancer Ther. 2005, 4: 32-44. 10.1177/1534735404273861.CrossRefPubMed
3.
go back to reference Klenner FR: The treatment of poliomyelitis and other virus diseases with vitamin C. South Med Surg. 1949, 111: 209-214.PubMed Klenner FR: The treatment of poliomyelitis and other virus diseases with vitamin C. South Med Surg. 1949, 111: 209-214.PubMed
4.
go back to reference Cameron E, Pauling L, Leibovitz B: Ascorbic acid and cancer: a review. Cancer Res. 1979, 39: 663-681.PubMed Cameron E, Pauling L, Leibovitz B: Ascorbic acid and cancer: a review. Cancer Res. 1979, 39: 663-681.PubMed
5.
go back to reference Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E, Levine M: Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci USA. 2005, 102: 13604-13609. 10.1073/pnas.0506390102.PubMedCentralCrossRefPubMed Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E, Levine M: Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci USA. 2005, 102: 13604-13609. 10.1073/pnas.0506390102.PubMedCentralCrossRefPubMed
6.
go back to reference Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E, Choyke PL, Pooput C, Kirk KL, Buettner GR, Levine M: Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci USA. 2007, 104: 8749-8754. 10.1073/pnas.0702854104.PubMedCentralCrossRefPubMed Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E, Choyke PL, Pooput C, Kirk KL, Buettner GR, Levine M: Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci USA. 2007, 104: 8749-8754. 10.1073/pnas.0702854104.PubMedCentralCrossRefPubMed
7.
go back to reference Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M: Intravenously administered vitamin C as cancer therapy: three cases. CMAJ. 2006, 174: 937-942.PubMedCentralCrossRefPubMed Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M: Intravenously administered vitamin C as cancer therapy: three cases. CMAJ. 2006, 174: 937-942.PubMedCentralCrossRefPubMed
9.
go back to reference de la Lastra CA, Villegas I: Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans. 2007, 35: 1156-1160. 10.1042/BST0351156.CrossRefPubMed de la Lastra CA, Villegas I: Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans. 2007, 35: 1156-1160. 10.1042/BST0351156.CrossRefPubMed
10.
11.
go back to reference Peyman GA, Kivilcim M, Morales AM, DellaCroce JT, Conway MD: Inhibition of corneal angiogenesis by ascorbic acid in the rat model. Graefes Arch Clin Exp Ophthalmol. 2007, 245: 1461-1467. 10.1007/s00417-007-0542-4.CrossRefPubMed Peyman GA, Kivilcim M, Morales AM, DellaCroce JT, Conway MD: Inhibition of corneal angiogenesis by ascorbic acid in the rat model. Graefes Arch Clin Exp Ophthalmol. 2007, 245: 1461-1467. 10.1007/s00417-007-0542-4.CrossRefPubMed
12.
go back to reference Park S, Ahn ES, Lee S, Jung M, Park JH, Yi SY, Yeom CH: Proteomic analysis reveals upregulation of RKIP in S-180 implanted BALB/C mouse after treatment with ascorbic acid. J Cell Biochem. 2009, 106: 1136-1145. 10.1002/jcb.22097.CrossRefPubMed Park S, Ahn ES, Lee S, Jung M, Park JH, Yi SY, Yeom CH: Proteomic analysis reveals upregulation of RKIP in S-180 implanted BALB/C mouse after treatment with ascorbic acid. J Cell Biochem. 2009, 106: 1136-1145. 10.1002/jcb.22097.CrossRefPubMed
13.
go back to reference Chomczynski P: aMK Short technical report. Modification of the TRIZOL reagent procedure for isolation of RNA from Polysaccharide-and proteoglycan-rich sources. Biotechniques. 1995, 19: 942-945.PubMed Chomczynski P: aMK Short technical report. Modification of the TRIZOL reagent procedure for isolation of RNA from Polysaccharide-and proteoglycan-rich sources. Biotechniques. 1995, 19: 942-945.PubMed
14.
go back to reference Lynch MJRS, Mellor LD, Spare PD, Inwood JH: Medical Laboratory Technology and Clinical Pathology. 1969, Philadelphia: W. B. Saunders Co, 2 Lynch MJRS, Mellor LD, Spare PD, Inwood JH: Medical Laboratory Technology and Clinical Pathology. 1969, Philadelphia: W. B. Saunders Co, 2
15.
go back to reference McLane MA, Zhang X, Tian J, Zelinskas C, Srivastava A, Hensley B, Paquette-Straub C: Scratching below the surface: wound healing and alanine mutagenesis provide unique insights into interactions between eristostatin, platelets and melanoma cells. Pathophysiol Haemost Thromb. 2005, 34: 164-168. 10.1159/000092417.CrossRefPubMed McLane MA, Zhang X, Tian J, Zelinskas C, Srivastava A, Hensley B, Paquette-Straub C: Scratching below the surface: wound healing and alanine mutagenesis provide unique insights into interactions between eristostatin, platelets and melanoma cells. Pathophysiol Haemost Thromb. 2005, 34: 164-168. 10.1159/000092417.CrossRefPubMed
16.
go back to reference Barness LA: Safety considerations with high ascorbic acid dosage. Ann N Y Acad Sci. 1975, 258: 523-528. 10.1111/j.1749-6632.1975.tb29311.x.CrossRefPubMed Barness LA: Safety considerations with high ascorbic acid dosage. Ann N Y Acad Sci. 1975, 258: 523-528. 10.1111/j.1749-6632.1975.tb29311.x.CrossRefPubMed
17.
go back to reference Mayland CR, Bennett MI, Allan K: Vitamin C deficiency in cancer patients. Palliat Med. 2005, 19: 17-20. 10.1191/0269216305pm970oa.CrossRefPubMed Mayland CR, Bennett MI, Allan K: Vitamin C deficiency in cancer patients. Palliat Med. 2005, 19: 17-20. 10.1191/0269216305pm970oa.CrossRefPubMed
18.
19.
20.
go back to reference Folkman J: Fundamental concepts of the angiogenic process. Curr Mol Med. 2003, 3: 643-651. 10.2174/1566524033479465.CrossRefPubMed Folkman J: Fundamental concepts of the angiogenic process. Curr Mol Med. 2003, 3: 643-651. 10.2174/1566524033479465.CrossRefPubMed
21.
go back to reference Di Blasio AM, Carniti C, Vigano P, Vignali M: Basic fibroblast growth factor and ovarian cancer. J Steroid Biochem Mol Biol. 1995, 53: 375-379. 10.1016/0960-0760(95)00082-B.CrossRefPubMed Di Blasio AM, Carniti C, Vigano P, Vignali M: Basic fibroblast growth factor and ovarian cancer. J Steroid Biochem Mol Biol. 1995, 53: 375-379. 10.1016/0960-0760(95)00082-B.CrossRefPubMed
22.
go back to reference Crickard K, Gross JL, Crickard U, Yoonessi M, Lele S, Herblin WF, Eidsvoog K: Basic fibroblast growth factor and receptor expression in human ovarian cancer. Gynecol Oncol. 1994, 55: 277-284. 10.1006/gyno.1994.1290.CrossRefPubMed Crickard K, Gross JL, Crickard U, Yoonessi M, Lele S, Herblin WF, Eidsvoog K: Basic fibroblast growth factor and receptor expression in human ovarian cancer. Gynecol Oncol. 1994, 55: 277-284. 10.1006/gyno.1994.1290.CrossRefPubMed
23.
go back to reference Montesano R, Vassalli JD, Baird A, Guillemin R, Orci L: Basic fibroblast growth factor induces angiogenesis in vitro. Proc Natl Acad Sci USA. 1986, 83: 7297-7301. 10.1073/pnas.83.19.7297.PubMedCentralCrossRefPubMed Montesano R, Vassalli JD, Baird A, Guillemin R, Orci L: Basic fibroblast growth factor induces angiogenesis in vitro. Proc Natl Acad Sci USA. 1986, 83: 7297-7301. 10.1073/pnas.83.19.7297.PubMedCentralCrossRefPubMed
24.
go back to reference Johnston CL, Cox HC, Gomm JJ, Coombes RC: bFGF and aFGF induce membrane ruffling in breast cancer cells but not in normal breast epithelial cells: FGFR-4 involvement. Biochem J. 1995, 306 (Pt 2): 609-616.PubMedCentralCrossRefPubMed Johnston CL, Cox HC, Gomm JJ, Coombes RC: bFGF and aFGF induce membrane ruffling in breast cancer cells but not in normal breast epithelial cells: FGFR-4 involvement. Biochem J. 1995, 306 (Pt 2): 609-616.PubMedCentralCrossRefPubMed
25.
go back to reference Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J: Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989, 84: 1470-1478. 10.1172/JCI114322.PubMedCentralCrossRefPubMed Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J: Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989, 84: 1470-1478. 10.1172/JCI114322.PubMedCentralCrossRefPubMed
26.
go back to reference Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992, 359: 845-848. 10.1038/359845a0.CrossRefPubMed Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992, 359: 845-848. 10.1038/359845a0.CrossRefPubMed
27.
go back to reference Ramakrishnan S, Olson TA, Bautch VL, Mohanraj D: Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-1-positive endothelial cell proliferation in vitro and angiogenesis in vivo. Cancer Res. 1996, 56: 1324-1330.PubMed Ramakrishnan S, Olson TA, Bautch VL, Mohanraj D: Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-1-positive endothelial cell proliferation in vitro and angiogenesis in vivo. Cancer Res. 1996, 56: 1324-1330.PubMed
28.
go back to reference Yamamoto S, Konishi I, Mandai M, Kuroda H, Komatsu T, Nanbu K, Sakahara H, Mori T: Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer. 1997, 76: 1221-1227.PubMedCentralCrossRefPubMed Yamamoto S, Konishi I, Mandai M, Kuroda H, Komatsu T, Nanbu K, Sakahara H, Mori T: Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer. 1997, 76: 1221-1227.PubMedCentralCrossRefPubMed
29.
go back to reference Karavasilis V, Malamou-Mitsi V, Briasoulis E, Tsanou E, Kitsou E, Kalofonos H, Fountzilas G, Fotsis T, Pavlidis N: Angiogenesis in cancer of unknown primary: clinicopathological study of CD34, VEGF and TSP-1. BMC Cancer. 2005, 5: 25-10.1186/1471-2407-5-25.PubMedCentralCrossRefPubMed Karavasilis V, Malamou-Mitsi V, Briasoulis E, Tsanou E, Kitsou E, Kalofonos H, Fountzilas G, Fotsis T, Pavlidis N: Angiogenesis in cancer of unknown primary: clinicopathological study of CD34, VEGF and TSP-1. BMC Cancer. 2005, 5: 25-10.1186/1471-2407-5-25.PubMedCentralCrossRefPubMed
30.
go back to reference Staack A, Badendieck S, Schnorr D, Loening SA, Jung K: Combined determination of plasma MMP2, MMP9, and TIMP1 improves the non-invasive detection of transitional cell carcinoma of the bladder. BMC Urol. 2006, 6: 19-10.1186/1471-2490-6-19.PubMedCentralCrossRefPubMed Staack A, Badendieck S, Schnorr D, Loening SA, Jung K: Combined determination of plasma MMP2, MMP9, and TIMP1 improves the non-invasive detection of transitional cell carcinoma of the bladder. BMC Urol. 2006, 6: 19-10.1186/1471-2490-6-19.PubMedCentralCrossRefPubMed
31.
go back to reference Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M: In vivo and in vitro antitumor effect of ascorbic acid, lysine, proline, arginine, and green tea extract on human fibrosarcoma cells HT-1080. Med Oncol. 2006, 23: 105-111. 10.1385/MO:23:1:105.CrossRefPubMed Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M: In vivo and in vitro antitumor effect of ascorbic acid, lysine, proline, arginine, and green tea extract on human fibrosarcoma cells HT-1080. Med Oncol. 2006, 23: 105-111. 10.1385/MO:23:1:105.CrossRefPubMed
32.
go back to reference Roomi MW, Ivanov V, Netke S, Kalinovsky T, Niedzwiecki A, Rath M: In vivo and in vitro antitumor effect of ascorbic acid, lysine, proline and green tea extract on human melanoma cell line A2058. In Vivo. 2006, 20: 25-32.PubMed Roomi MW, Ivanov V, Netke S, Kalinovsky T, Niedzwiecki A, Rath M: In vivo and in vitro antitumor effect of ascorbic acid, lysine, proline and green tea extract on human melanoma cell line A2058. In Vivo. 2006, 20: 25-32.PubMed
33.
go back to reference Roomi MW, Roomi N, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M: Inhibitory effect of a mixture containing ascorbic acid, lysine, proline and green tea extract on critical parameters in angiogenesis. Oncol Rep. 2005, 14: 807-815.PubMed Roomi MW, Roomi N, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M: Inhibitory effect of a mixture containing ascorbic acid, lysine, proline and green tea extract on critical parameters in angiogenesis. Oncol Rep. 2005, 14: 807-815.PubMed
34.
go back to reference Ashino H, Shimamura M, Nakajima H, Dombou M, Kawanaka S, Oikawa T, Iwaguchi T, Kawashima S: Novel function of ascorbic acid as an angiostatic factor. Angiogenesis. 2003, 6: 259-269. 10.1023/B:AGEN.0000029390.09354.f8.CrossRefPubMed Ashino H, Shimamura M, Nakajima H, Dombou M, Kawanaka S, Oikawa T, Iwaguchi T, Kawashima S: Novel function of ascorbic acid as an angiostatic factor. Angiogenesis. 2003, 6: 259-269. 10.1023/B:AGEN.0000029390.09354.f8.CrossRefPubMed
36.
37.
go back to reference Frei B, England L, Ames BN: Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA. 1989, 86: 6377-6381. 10.1073/pnas.86.16.6377.PubMedCentralCrossRefPubMed Frei B, England L, Ames BN: Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA. 1989, 86: 6377-6381. 10.1073/pnas.86.16.6377.PubMedCentralCrossRefPubMed
38.
go back to reference Levine M, Dhariwal KR, Washko PW, Butler JD, Welch RW, Wang YH, Bergsten P: Ascorbic acid and in situ kinetics: a new approach to vitamin requirements. Am J Clin Nutr. 1991, 54: 1157S-1162S.PubMed Levine M, Dhariwal KR, Washko PW, Butler JD, Welch RW, Wang YH, Bergsten P: Ascorbic acid and in situ kinetics: a new approach to vitamin requirements. Am J Clin Nutr. 1991, 54: 1157S-1162S.PubMed
39.
go back to reference Niki E: Action of ascorbic acid as a scavenger of active and stable oxygen radicals. Am J Clin Nutr. 1991, 54: 1119S-1124S.PubMed Niki E: Action of ascorbic acid as a scavenger of active and stable oxygen radicals. Am J Clin Nutr. 1991, 54: 1119S-1124S.PubMed
40.
go back to reference Mirvish SS: Experimental evidence for inhibition of N-nitroso compound formation as a factor in the negative correlation between vitamin C consumption and the incidence of certain cancers. Cancer Res. 1994, 54: 1948s-1951s.PubMed Mirvish SS: Experimental evidence for inhibition of N-nitroso compound formation as a factor in the negative correlation between vitamin C consumption and the incidence of certain cancers. Cancer Res. 1994, 54: 1948s-1951s.PubMed
41.
go back to reference Eckardt KU, Bernhardt W, Willam C, Wiesener M: Hypoxia-inducible transcription factors and their role in renal disease. Semin Nephrol. 2007, 27: 363-372. 10.1016/j.semnephrol.2007.02.007.CrossRefPubMed Eckardt KU, Bernhardt W, Willam C, Wiesener M: Hypoxia-inducible transcription factors and their role in renal disease. Semin Nephrol. 2007, 27: 363-372. 10.1016/j.semnephrol.2007.02.007.CrossRefPubMed
42.
go back to reference Jones DT, Trowbridge IS, Harris AL: Effects of transferrin receptor blockade on cancer cell proliferation and hypoxia-inducible factor function and their differential regulation by ascorbate. Cancer Res. 2006, 66: 2749-2756. 10.1158/0008-5472.CAN-05-3857.CrossRefPubMed Jones DT, Trowbridge IS, Harris AL: Effects of transferrin receptor blockade on cancer cell proliferation and hypoxia-inducible factor function and their differential regulation by ascorbate. Cancer Res. 2006, 66: 2749-2756. 10.1158/0008-5472.CAN-05-3857.CrossRefPubMed
43.
go back to reference Drisko JA, Chapman J, Hunter VJ: The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr. 2003, 22: 118-123.CrossRefPubMed Drisko JA, Chapman J, Hunter VJ: The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr. 2003, 22: 118-123.CrossRefPubMed
Metadata
Title
High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis
Authors
Chang-Hwan Yeom
Gunsup Lee
Jin-Hee Park
Jaelim Yu
Seyeon Park
Sang-Yeop Yi
Hye Ree Lee
Young Seon Hong
Joosung Yang
Sukchan Lee
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2009
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-7-70

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