Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

HMG–CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: Lovastatin specifically targets P–glycoprotein–expressing cells

Abstract

The enzyme 3–hydroxy–3–methylglutaryl coenzyme A (HMG–CoA) reductase, involved in de novo cholesterol synthesis and cell–cycle progression, was identified as a potential mediator of the growth inhibitory effects of retinoic acid on human neuroblastoma. Lovastatin, a nonreversible inhibitor of HMG–CoA reductase, induced extensive cytotoxicity that was restricted to drug–resistant P–glycoprotein–expressing neuroblastoma cell lines. This response was potentiated by dibutyryl cyclic AMP but not retinoic acid. Patients with advanced–stage metastatic neuroblastoma often display an acquired chemoresistant phenotype, which may in part be mediated by P–glycoprotein. Our studies support the application or use of HMG–CoA reductase inhibitors as potential therapeutic agents in the treatment of these patients who are refractory to chemotherapy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Adam, A. & Hocholzer, L. Ganglioneuroblastoma of the posterior mediastinum. Cancer 47, 373–381 (1983).

    Article  Google Scholar 

  2. Bolande, R.P. Spontaneous regression and cytodifferentiation of cancer in early life: the oncogenic grace period. Surv. Synthet. Pathol. Res. 4, 296–311 (1985).

    CAS  Google Scholar 

  3. Evans, A.E., Gerson, J. & Schnanfer, L. Spontaneous regression of neuroblastoma. Natl. Cancer Inst. Monogr. 44, 49–54 (1976).

    CAS  PubMed  Google Scholar 

  4. Shimada, H. et al. Histopathologic prognostic factors on neuroblastic tumors: Definition of subtypes of ganglioneuroblastoma and age-linked classification of neuroblastoma. J. Natl. Cancer Inst. 73 405–416 (1984).

    Article  CAS  Google Scholar 

  5. Tsokos, M., Scarpa, S., Ross, R.A. & Triche, T.J. Differentiation of human neuroblastoma recapitulates neural crest development. Am. J. Pathol. 128, 484–496 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Yeger, H. et al. Phenotypic and molecular characterization of inducible human neuroblastoma cell lines. Differentiation 39, 216–227 (1988).

    Article  CAS  Google Scholar 

  7. Woods, W.G., Lemieux, B. & Tuchman, M. Neuroblastoma represents distinct clinical-biological entities: A review and perspective from the Quebec neuroblastoma screening project. Pediatrics 89, 114–118 (1992).

    CAS  PubMed  Google Scholar 

  8. Goldstein, L.J. et al. Expression of the multidrug resistance, MDR1, gene in neuroblastoma. J. Clin. Oncol. 8, 128–136 (1990).

    Article  CAS  Google Scholar 

  9. Bardow, S.B. et al. Expression of the multidrug resistance-associated protein (MRP). gene correlates with amplification and overexpression of the N-myconcogene in childhood neuroblastoma. Cancer Res. 54, 5036–5040 (1994).

    Google Scholar 

  10. Gottesman, M.M. & Pastan, I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62, 385–427 (1993).

    Article  CAS  Google Scholar 

  11. Chan, H.S.L. et al. P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N. Engl. J. Med. 325, 1608–1614 (1991).

    Article  CAS  Google Scholar 

  12. Bourhis, J. et al. Correlation of MDR1 gene expression with chemotherapy in neuroblastoma. J. Natl. Cancer Inst. 81, 1401–1405 (1989).

    Article  CAS  Google Scholar 

  13. Dimitroulakos, J., Squire, J., Pawlin, G. & Yeger, H. NUB-7: A stable I-type human neuroblastoma cell line inducible along N- and S-type cell lineages. Cell Growth Differ. 5, 373–384 (1994).

    CAS  PubMed  Google Scholar 

  14. Liang, P. & Pardee, A.B. Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 257, 967–971 (1992).

    Article  CAS  Google Scholar 

  15. Goldstein, J.L. & Brown, M.S. Regulation of the mevalonate pathway. Nature 343, 425–430 (1990).

    Article  CAS  Google Scholar 

  16. Corsini, A., Maggi, F.M. & Catapano, A.L. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol. Res. 31, 9–27 (1995).

    Article  CAS  Google Scholar 

  17. Ramharack, R., Tam, S.P. & Deeley, R.G. Characterization of three distinct size classes of human 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA: Expression of the transcripts in hepatic and nonhepatic cells. DNA Cell Biol. 9, 677–690 (1990).

    Article  CAS  Google Scholar 

  18. Wimalasena, J., Meehan, D. & Cavallo, C. Human epithelial ovarian cancer cell steroid secretion and its control by gonadotrophins. Gynecol. Oncol. 41, 56–63 (1991).

    Article  CAS  Google Scholar 

  19. Kleinert, R. Immunohistochemical characterization of primitive neuroectodermal tumors and their possible relationship to the stepwise ontogenic development of the central nervous system. Acta Neuropathol. 82, 502–515 (1991).

    Article  CAS  Google Scholar 

  20. Thiele, C.J., Reynolds, C.P. & Israel, M.A. Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma. Nature 313, 404–406 (1985).

    Article  CAS  Google Scholar 

  21. Arey, J.B. The lipidoses: Morphologic changes in the nervous system in Gaucher's disease, GM2-gangliosidoses and Neimann-Pick disease. J. Clin. Lab. Sci. 5, 475–482 (1975).

    CAS  Google Scholar 

  22. Kerr, J.F.R., Winterford, C.M. & Harmon, B.V., Its clinical significance in cancer and cancer therapy. Cancer 73, 2013–2026 (1994).

    Article  CAS  Google Scholar 

  23. Piacentini, M., Fesus, L. & Melino, G. Multiple cell cycle access to the apoptotic death programme in human neuroblastoma cells. FEBS Lett. 320, 150–154 (1993).

    Article  CAS  Google Scholar 

  24. Keyomarsi, K., Sandoval, L., Band, V. & Pardee, A.B. Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res. 51, 3602–3609 (1991).

    CAS  PubMed  Google Scholar 

  25. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Meth. 65, 55–63 (1983).

    Article  CAS  Google Scholar 

  26. Ramani, P. & Dewchand, H. Expression of mdrl/P-glycoprotein and p110 in neuroblastoma. J. Pathol. 175, 13–22 (1995).

    Article  CAS  Google Scholar 

  27. Rocchi, P. et al. Growth inhibitory and differentiating effects of sodium butyrate on human neuroblastoma cells in culture. Anticancer Res. 12, 917–920 (1992).

    CAS  PubMed  Google Scholar 

  28. Gibbs, J.B., C-terminal processing enzymes — new drug targets? Cell 65, 1–4 (1991).

    Article  CAS  Google Scholar 

  29. Kohl, N.E. et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nature Med. 1, 792–797 (1995).

    Article  CAS  Google Scholar 

  30. Maltese W.A. Inhibitation of farneysltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice Nature Med. 1 792 – 797 (1995).

    Article  Google Scholar 

  31. DeLuca, L. Retinoids and their receptors in differentiation, embryogenesis and neoplasia. FASEB J. 5, 2924–2933 (1991).

    Article  CAS  Google Scholar 

  32. Britton, G. Structure and properties of carotenoids in relation to function. FASEB J. 9 1551–1558 (1995).

    Article  CAS  Google Scholar 

  33. Karp, J.E. & Broder, S. Molecular foundations of cancer: New targets for intervention. Nature Med. 1, 309–320 (1995).

    Article  CAS  Google Scholar 

  34. Gottesman, M.M. The role of cAMP in regulating tumor cell growth. Cancer Surv. 5, 291–308 (1986).

    CAS  PubMed  Google Scholar 

  35. Gaetano, C., Matsumoto, K. & Thiele, C.J. In vitro activation of distinct molecular and cellular phenotypes after induction of differetiation in a human neuroblastoma cell line. Cancer Res. 52, 4402–407 (1992).

    CAS  PubMed  Google Scholar 

  36. Maltese, W.A., Defendini, R., Green, R.A., Sheridan, K.M. & Donley, D.K. Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive in hibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. J. Clin. Invest. 76 1748–1754 (1985).

    Article  CAS  Google Scholar 

  37. Chervinsky, D.S., Brecher, M.L. & Hoelcle, M.J. Cremophor-EL enhances taxol efficacy in a multidrug resistant C1300 neuroblastoma cell line. Anticancer Res. 13 93–96 (1993).

    CAS  PubMed  Google Scholar 

  38. Holmberg, M., Sandberg, C., Nygren, P. & Larsson, R. Effects of lovastatin on a human myeloma cell line: Increased sensitivity of a multidrug resistant subline that expresses P-glycoprotein. Anti-cancer Drugs 5, 598–600 (1994).

    Article  CAS  Google Scholar 

  39. Tsujita, Y. et al. CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: Tissue selective inhibitor of of sterol synthesis and hypolipidemic effect on various animal species. Biochim. Biophys. Acta 877, 50–60 (1986).

    Article  CAS  Google Scholar 

  40. Lange, Y. & Steck, T.L. Cholesterol homeostasis: modulation by amphiphiles. J. Biol. Chem. 269, 29371–29374 (1994).

    CAS  PubMed  Google Scholar 

  41. Abermayor, E. The effects of retinoic acid on the in vitro and in vivo growth of neuroblastoma cells. Laryngoscope 102, 1133–1149 (1992).

    Article  Google Scholar 

  42. O'Dorisio, M.S., Fleshman, D.J., Qualman, S.J. & O'Dorisio, T.M. Vasoactive intestinal peptide: autocrine growth factor in neuroblastoma. Regul. Pept. 37 231–236 (1992).

    Google Scholar 

  43. Helson, L., Kelson, C., Peterson, R.F. & Susanta, K.D. A rationale for the treatment of metastatic neuroblastoma. J. Natl. Cancer Inst. 57, 727–729 (1976).

    Article  CAS  Google Scholar 

  44. Yeger, H., Mor, O., Pawlin, G., Kaplinsky, C. & Shiloh, Y. Importance of phenotypic and molecular characterization for identification of a neuroepithelioma tumor cell line, NUB-20. Cancer Res. 50, 2794–2802 (1990).

    CAS  PubMed  Google Scholar 

  45. Seeger, R.C. et al. Morphology, growth, chromosomal pattern, and fibrinolytic activity of two new human neuroblastoma cell lines. Cancer Res. 37 1364–1371 (1977).

    CAS  PubMed  Google Scholar 

  46. Murakami, T., Ohmori, H., Tsuda, T. & Higashi, K. The effect of changes in the N-myc products on the gene expression of heat shock protein (HSP-70). and nucleolin during differentiation of neuroblastoma cells. Progr. Clin. Biol. Res. 366 65–70 (1991).

    CAS  Google Scholar 

  47. Sekiguchi, M., Oota, T., Sakakibara, K., Inui, N. & Fujii, G. Establishment and characterization of a human neuroblastoma cell line in tissue culture. Jpn. J. Exp. Med. 49, 67–83 (1979).

    CAS  PubMed  Google Scholar 

  48. Imashuka, S., Inui, A., Nakamura, T., Tanaka, J. & Miyake S. Catecholamine metabolism in tissue culture cells of a neuroblastoma. J. Clin. Endocrinol. Metab. 36 931–936 (1973).

    Article  Google Scholar 

  49. Cohn, S.L. et al. High levels of N-myc protein in a neuroblastoma cell line lacking N-myc amplification. Progr. Clin. Biol. Res. 366, 21–27 (1991).

    CAS  Google Scholar 

  50. Biedler, J.L., Helson, L. & Spengler, B.A. Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continous culture. Cancer Res. 33, 2643–2652 (1973).

    CAS  PubMed  Google Scholar 

  51. Tumilowicz, J.J., Nichols, W.W., Cholon, J.J. & Greene, A.E. Definition of a continuous cell line derived from neuroblastoma. Cancer Res. 30, 2110–2118 (1970).

    CAS  PubMed  Google Scholar 

  52. Keyomarsi, K., Sandoval, L., Band, V. & Pardee, A.B. Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res. 51, 3602–3609 (1991).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dimitroulakos, J., Yeger, H. HMG–CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: Lovastatin specifically targets P–glycoprotein–expressing cells. Nat Med 2, 326–333 (1996). https://doi.org/10.1038/nm0396-326

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0396-326

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing