Skip to main content
Log in

Antiproliferative and apoptotic effect of ascorbyl stearate in human glioblastoma multiforme cells: modulation of insulin-like growth factor-I receptor (IGF-IR) expression

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Human glioblastomas (gliomas) are characterized as highly invasive and rapidly growing brain tumors. In this study, we present data on in vitro effect of ascorbyl stearate (Asc-S), a liphophilic derivative of ascorbic acid on cell proliferation, transformation, apoptosis and modulation of expression of insulin-like growth factor-I receptor (IGF-IR) in human glioblastoma multiforme (T98G) cells. Asc-S showed significant inhibition of fetal bovine serum and human recombinant insulin-like growth factor-I (IGF-I) dependent cell proliferation in a dose dependent manner. Treatment of T98G cells with 0, 50, 100 and 150 μM Asc-S for 24 h slowed down the cell multiplication cycle with significant accumulation of cells at late S/G2-M phase of cycle. Asc-S treatment (100 μM) reversed the transformed phenotype as determined by clonogenecity in soft agar and also induced apoptosis of T98G. These changes were found to be associated with significant decrease in IGF-IR expression in dose and time dependent manner compared to untreated controls. The data clearly demonstrate that Asc-S has antiproliferative and apoptotic effect on T98G cells probably through modulation of IGF-IR expression and consequent facilitation of programmed cell death.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Russel DS, Rubenstein LJ: Pathology of Tumors of the Nervous System, 5th edn. Baltimore, Williams & Wilkins, 1989

    Google Scholar 

  2. Black PM: Brain tumors (Parts I and II). N Engl J Med 324: 1471–1476, 1991

    Google Scholar 

  3. Mahaley MS Jr: Neuro-oncology index and review (Adult primary brain tumors radiotherapy, chemotherapy, immunotherapy, photodynamic therapy). J Neuro-Oncol 11: 85–147, 1991

    Google Scholar 

  4. Greenle GT, Murray T, Bolden S, Wingo PA: Cancer statistics 2000. CA Cancer J Clin 50: 7–33, 2000

    Google Scholar 

  5. Leung PY, Miyashita K, Young M, Tsao CS: Cytotoxic effect of ascorbate and its derivatives on cultured malignant and nonmalignant cell line. Anticancer Res 13: 475–480, 1993

    Google Scholar 

  6. Roomi MW, House D, Eckert-Maksic M, Masksic ZB, Tsao CS: Growth suppression of malignant leukemia cell line in vitro by ascorbic acid (vitamin C) and its derivatives. Cancer Lett 122: 93–99, 1998

    Google Scholar 

  7. Habib NA, Wood CB, Apostolov K, Barker W, Hershman MJ, Aslam M, Heinemenn D, Fermor B, Williamson RCN, Jenkins WE, Masters JRW, Embleton MJ: Stearic acid and carcinogenesis. Brit J Cancer 56: 455–458, 1987

    Google Scholar 

  8. Pauling L: Effect of ascorbic acid on incidence of spontaneous mammary tumors and UV light induced skin tumors in mice. Am J Clin Nutr 54: 1252S–1255S, 1991

    Google Scholar 

  9. Ibric LLV, Peterson AR, Sevanian A: Mechanism of ascorbic acid induced inhibition of chemical transformation in C3H/1OT1/2 cells. Am J Clin Nutr 54: 1236S–1240S, 1991

    Google Scholar 

  10. Block G: Vitamin C and cancer prevention: the epidemiological evidence. Am J Cin Nutr 53: 270S–282S, 1991

    Google Scholar 

  11. Liehr JG: Vitamin C reduces the incidence and severity of renal tumors induced by estradiol and deithylstilbesterol. Am J Clin Nutr 54: 1256S–1260S, 1991

    Google Scholar 

  12. Mitra A, Govindwar S, Kulkarni AP: Inhibition of hepatic glutathione S-transferase by fatty acids and fatty acid esters. Toxicol Lett 58: 135–141, 1991

    Google Scholar 

  13. Mitra A, Govindwar S, Joseph P, Kulkarni AP: Inhibition of Human placental and fetal liver glutathione S-transferase by fatty acids and fatty acid esters. Toxicol Lett 60: 281–288, 1992

    Google Scholar 

  14. Banks WA, Kastin AJ: Peptides and blood-brain barrier: liphophilicity as predictor of permeability. Brain Res Bull 15: 287–292, 1985

    Google Scholar 

  15. Naidu AK, Wiranowska M, Kori SH, Roetzheim KC, Kulkarni AP: Inhibition of human glioma cell proliferation and glutathione S-transferase by ascorbyl esters and interferon. Anticancer Res 13: 1469–1471, 1993

    Google Scholar 

  16. Naidu AK, Wiranowska M, Kori SH, Prockop LD, Kulkarni AP: Inhibition of human glioma cell proliferation and glutathione S-transferase by ascorbyl esters and interferon in mouse glioma. J Neuro-Oncol 16: 1–10, 1993

    Google Scholar 

  17. Zumkeller W, Biernoth R, Kocialkowski S, Martinerie C, Schofield PN, Perbal B, Westphal M: Expression and synthesis of insulin-like growth factor (IGF)-I,-II and their receptors in human glioma cell lines. Int J Oncol 9: 983–992, 1998

    Google Scholar 

  18. Sandberg-Norquist AC, Stahlborn PA, Reinecke M, Collins VP, vonHolst H, Sara V: Characterization of insulin-like growth factor-I in human primary tumors. Cancer Res 53: 2475–2478, 1993

    Google Scholar 

  19. Sell C, Dumenil G, Devaud C, Miura M, Coppola D, De Angelis T, Efstratiadia A, Beserga R: Effect of a null mutation of the type 1 IGF receptor gene on growth and transformation of mouse embryo fibroblast. Mol Cell Biol 14: 3604–3612, 1994

    Google Scholar 

  20. Eckert-Maksic M, Kovacek ZB, Maksic M, Osmak KP: Effect of ascorbic acid and its derivatives on different tumors in vivo and in vitro, In: Maksic ZB, Eckert Maksic M (eds) Molecules in Natural Science and Medicine. An Encomium for Linus Pauling Ellis Horwood. New York, 1991, pp 509–524

  21. Makino Y, Sakagami H, Takeda M: Induction of cell death by ascorbic acid derivatives in human renal carcinoma and glioblastoma cell lines. Anticancer Res 19: 3125–3132, 1999

    Google Scholar 

  22. Baserga R, Hongo A, Rubin M, Prisco M, Valentinis B: The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1332: 105–126, 1997

    Google Scholar 

  23. Coppola D, Ferber A, Miura M, Sell C, D'Ambrosio C, Rubin R, Baserga R: A functional insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the epidermal growth factor receptor. Mol Cell Biol 14: 4588–4595, 1994

    Google Scholar 

  24. De Angelis T, Ferber A, Baserga R: Insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the platelet-derived growth factor receptor. J Cell Physiol 164: 214–221, 1995

    Google Scholar 

  25. Pardee AB: GI events and regulation of cell proliferation. Science 246: 603–605, 1989

    Google Scholar 

  26. Bijur GN, Briggs B, Hitchcock CL, Williams MV: Ascorbic acid-dehydroascorbate induces cell cycle arrest G2/M DNA damage check point during oxidative stress. Environ Mol Mutagen 33: 144–152, 1999

    Google Scholar 

  27. Sara VR, Carlsson-Skwirut C: The role of insulin-like growth factors in the regulation of brain development. Prog Brain Res 73: 87–99, 1988

    Google Scholar 

  28. Baskin DG, Wilcox BJ, Figlewicz DP, Dorsa DM: Insulin-like growth factors in CNS. Trends Neurosci 11: 107–111, 1988

    Google Scholar 

  29. LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr: Molecular and cellular aspects of insulin-like growth factor I receptor. Endocrine Rev 16: 143–163, 1995

    Google Scholar 

  30. Butler AA, Yakar S, Gewolb IH, Karas M, Okubo Y, LeRoith D: Insulin like growth factor-I receptor signal transduction: At the interface between physiology and cell biology. Comp Biochem Physiol B Biochem Mol Biol 121: 19–26, 1998

    Google Scholar 

  31. Petley T, Graff K, Jiang W, Yang H, Florini J: Variation among cell types in the signaling pathways by which IGF-I stimulates specific cellular responses. Horm Metab Res 31: 70–76, 1999

    Google Scholar 

  32. Valentinis B, Romano G, Peruzzi F, Morrione A, Prisco M, Soddu S, Cristofanelli B, Sacchi A, Baserga R: Growth and differentation signals by the insulin-like growth factor I receptor in hemopoietic cells are mediated through different pathways. J Biol Chem 274: 12423–12430, 1999

    Google Scholar 

  33. Resnicoff M, Burgaud JL, Rotman HL, Abraham D, Baserga R: Correlation between apoptosis, tumorigenesis and levels of insulin-like growth factor I receptors. Cancer Res 55: 3739–3741, 1995

    Google Scholar 

  34. Gammeltoft S, Ballotti R, Kowalski A, Westermark B, Van Obberghen E: Expression of two types of receptor for insulin-like growth factors in human malignant gliomas. Cancer Res 48: 1233–1237, 1988

    Google Scholar 

  35. Glick RP, Gettleman R, Patel K, Lakshman R, Tsibris JCM: Insulin and insulin-like growth factor I in brain tumors: binding and in vitro effects. Neurosurgery 24, 791–797, 1989

    Google Scholar 

  36. Merrill MJ, Edwards NA: Insulin-like growth factor-I receptors in human glial tumors. J Clin Endo Metab 71: 199–209, 1990

    Google Scholar 

  37. Sandberg Ac, Engberg C, Lake M, von Holst H, Sara VR: The expression of insulin-like growth factor I and insulin-like growth factor genes in human fetal and adult brain and glioma. Neurosci Lett 93: 114–119, 1988

    Google Scholar 

  38. Trojan J, Jhonson TR, Rudin SD, Ilan J, Tykocinski M, Ilan J: Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor 1 RNA. Science 259: 94–97, 1993

    Google Scholar 

  39. Resnicoff M, Sell C, Rubini R, Coppola D, Ambrose D, Baserga R, Rubin R: Rat glioblastoma cell expressing an antisense RNA to the insulin-like growth factor-I (IGF-I) receptor are nontumourigenic and induce regression of wild type tumors. Cancer Res 54: 2218–2222, 1994

    Google Scholar 

  40. Resnicoff M, Li W, Basak S, Heryln D, Baserga R, Rubin R: Inhibition of rat C6 glioblastoma tumor growth by expression of insulin-like growth factor-I receptor antisense mRNA. Cancer Immunol Immunother 42: 64–68, 1996

    Google Scholar 

  41. Ambrose D, Resnicoff M, Coppola D, Sell C, Miura C, Jameson S, Beserga R, Rubini R: Growth regulation of human glioblastoma T98G cells by insulin like-growth factor-1 and its receptor. J Cell Physiol 159: 92–100, 1994

    Google Scholar 

  42. Rininsland F, Hohnson TR, Chernicky CL, Schulze E, Burteind O, Ilan J: Suppression of insulin like-growth factor type I receptor by a triplex-helix strategy inhibits IGF-I transcription and tumorigenic potential of rat C6 glioblastoma cells. Proc Natl Acad Sci USA 94: 5854–5859, 1997

    Google Scholar 

  43. Park CH, Mammo A, Savin MA, Hoogstraten B: Growth suppression of human leukemia cell in vivo by l-ascorbic acid. Cancer Res 40: 1062–1065, 1980

    Google Scholar 

  44. Tsao CS: Inhibiting effect of ascorbic acid on growth of human mammary tumor xenografts. Am J Clin Nutr 54: 1274S–1280S, 1991

    Google Scholar 

  45. Medina MA, De Vegas RG, Schweigerer B: Ascorbic acid is cytotoxic for pedioatric tumor cells cultured in vitro. Biochem Mol Biol Inter 34: 871–874, 1994

    Google Scholar 

  46. Drake IM, Davies MJ, Mapstone NP, Dixon MF, Schorah CJ, White KL, Chalmers Dm, Axon AT: Ascorbic acid may protect against human gastric cancer by scavenging mucosal oxygen radicals. Carcinogenesis 17: 559–562, 1996

    Google Scholar 

  47. Sakagami H, Satoh K, Kochi M: Comparitive study of the antitumor action between sodium 5,6-benzylidene-lascorbate and sodium ascorbate (mini review). Anticancer Res 17: 4451–4452, 1997

    Google Scholar 

  48. Roomi MW, House D, Tsao CS: Cytotoxic effect of substitution at 2-,6-, and 2,6-positions in ascorbic acid on malignant cell line. Cancer Biochem Biophys 16: 295–300, 1998

    Google Scholar 

  49. Kaneko T, Kaji K, Mastuo M: Protective effect of liphophilic derivatives of ascorbic acid on lipid peroxide-induced endothelial injury. Arch Biochem Biophys 304(1): 176–180, 1993

    Google Scholar 

  50. Sakagami H, Satoh K, Ohata H, Takahashi H, Iida M, Kuribayashi N, Sakagami T, Momose K, Takeda M: Relationship between ascorbyl radical intensity and apoptosis-inducing activity. Anticancer Res 16: 2635–2644, 1996

    Google Scholar 

  51. Sakagami H, Satoh K, Hakeda Y, Kumegawa M: Apoptosis inducing activity of vitamin C and K. Cell Mol Biol (Noisy-le-grand) 46: 129–143, 2000

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Naidu, K.A., Liu Tang, J., Akhilender Naidu, K. et al. Antiproliferative and apoptotic effect of ascorbyl stearate in human glioblastoma multiforme cells: modulation of insulin-like growth factor-I receptor (IGF-IR) expression. J Neurooncol 54, 15–22 (2001). https://doi.org/10.1023/A:1012545311054

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1012545311054

Navigation