Skip to main content
NCBI home page
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1994 Jan;120(Suppl 1):S19–S22. doi: 10.1007/BF01377118

Coumarin modulates the cell-cycle progression of an MTV-EJras cell line

J Kahn 1, P Preis 2, F Waldman 3, A Tseng Jr 4,✉
PMCID: PMC12200375  PMID: 8132697

Abstract

The effects of coumarin (1,2-benzopyrone) onras oncogene expression during the cell cycle of an MTV-EJras cell line was determined by flow cytometry.ras oncogene expression in cells was induced by dexamethasone and increased fivefold during G1/G0 phase and threefold in S phase. Dexamethasone also increased the percentage of cells in S phase from 21% to 31%, compared to phosphate-buffered-saline-treated control cells (P<0.01). Coumarin decreased the percentage of dexamethasone-treated cells in S phase from 31% to 19%, with a concomitant increase in the percentage of cells in G1/G0 compared to control levels. Coumarin also reducedras expression (mean fluorescence) by 40% in G1/G0 phase and 30% in S phase. We conclude that coumarin significantly reduces the cell-cycle progression of MTV-EJras cells and decreasesras expression in both G1 and S phases. These findings suggest a novel approach to the selective control of proliferation of malignant cells.

Key words: ras, Cell cycle, Coumarin

References

  1. Andreef M, Slater DE, Bressler J, Furth ME (1986) Cellularras oncogene expression and cell cycle measured by flow cytometry in hematopoietic cell lines. Blood 3:676–681 [PubMed] [Google Scholar]
  2. Balmain A, Ramsden M, Bowden GT, Smith J (1984) Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307:658–660 [DOI] [PubMed] [Google Scholar]
  3. Campisi J, Gray HE, Pardee AB, Dean M, Sonenshein GE (1984) Cell-cycle control of c-myc but not c-ras expression is lost following chemical transformation. Cell 36:241–247 [DOI] [PubMed] [Google Scholar]
  4. Dolbeare F, Gratzner H, Pallavicini MG, Gray JW (1983) Flow cytometric measurement of total DNA content and incorporated bromodeoxyuridine. Proc Natl Acad Sci USA 80:5573–5577 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Durkin JP, Whitfield JF (1986) Characterization of G1 transit induced by the mitogenic-oncogenic viral Ki-ras gene product. Mol Cell Biol 6:1386–1392 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Furth ME, Davis LJ, Fleurdelys B, Scolnick EM (1982) Monoclonal antibodies to the p21 products of the transforming gene of Harvey murine sarcoma virus and of the cellularras gene family. Virology 73:294–304 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Marshall EM, Mendelsohn L, Butler K, Riley L, Contrell J, Wiseman C, Taylor R, MacDonald JS (1987) Treatment of metastic renal cell cancer with coumarin (1,2-benzopyrone) and cimetidine: a pilot study. J Clin Oncol 5:862–866 [DOI] [PubMed] [Google Scholar]
  8. Miller RG (1986) Beyond anova, basics of applied statistics. Wiley, New York [Google Scholar]
  9. Milo GE, Kurian P, Kirsten E, Kun E (1985) Inhibition of carcinogen-induced cellular transformation of human fibroblasts by drugs that interact with the poly(ADP-ribose) polymerase system. FEBS Lett 179:332–336 [DOI] [PubMed] [Google Scholar]
  10. Mulcahy LS, Smith MR, Stacey DW (1985) Requirement forras proto-oncogene function during serum stimulated growth of NIH 3T3 cells. Nature 313:241–243 [DOI] [PubMed] [Google Scholar]
  11. Newbold RF, Overell RW (1984) Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Science 310:628–629 [DOI] [PubMed] [Google Scholar]
  12. Parada L, Tabin CJ, Shih C, Weinber RA (1982) Human EJ, bladder carcinoma oncogene is a homologue of Harvey sarcoma virusras gene. Nature 295:474–478 [DOI] [PubMed] [Google Scholar]
  13. Pardee AB (1987) Molecules involved in proliferation of normal and cancer cells: presidential address. Cancer Res 47:1488–1491 [PubMed] [Google Scholar]
  14. Pardee AB (1989) G1 events and regulation of cell proliferation. Nature 246:603–608 [DOI] [PubMed] [Google Scholar]
  15. Philips AR, Pillinger MH, Staud R, Volker C, Rosenfeld MG, Weissmann G, Stock JF (1993) Carboxyl methylation ofras-related proteins during signal transduction in neutrophils. Science 259:977–980 [DOI] [PubMed] [Google Scholar]
  16. Schafer WR, Kim R, Sterne R, Thorner J, Kim SH, Rine J (1989) Genetic and pharmacologic suppression of oncogenic mutations in RAS genes of yeast and humans. Science 245:379–385 [DOI] [PubMed] [Google Scholar]
  17. Thornes RD, Lynch G, Sheehan MV (1982) Cimetidine and coumarin therapy of melanoma. Lancet 2:326 [DOI] [PubMed] [Google Scholar]
  18. Tseng A (1993) Coumarin prevents tumorigenesis in MTV-H-ras transgenic mice. J Ir Coll Physicians and Surgeons [Suppl 1] 22:49–50 [Google Scholar]
  19. Tseng A, Lee WMF, Kirsten E, Hakam A, Mc Lick J, Buki K, Kun E (1987) Prevention of tumorigenesis of oncogene-transformed rat fibroblasts with DNA site inhibitors of poly(ADP ribose) polymerase. Proc Natl Acad Sci USA 84:1107–1111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Varmus HE (1984) The molecular genetics of cellular oncogenes. Annu Rev Genet 18:553–612 [DOI] [PubMed] [Google Scholar]
  21. Waldman F, Dolbeare F, Gray JW (1985) Detection of cytosine arabinoside resistant cells at low frequency using bromodeoxyuridine/DNA assay. Cytometry 6:657–662 [DOI] [PubMed] [Google Scholar]
  22. Wattenberg, LW, Lam LKT, Fladmoe AV (1979) Inhibition of chemical carcinogen-induced neoplasia by coumarins and alpha-angelicalactone. Cancer Res 39:1651–1654 [PubMed] [Google Scholar]
  23. Young HA, Klein RA, Shih TY, Morgan AC, Schroff RW (1986) Detection of the intracellularras p21 oncogene product by flow cytometry. Anal Biochem 156:67–71 [DOI] [PubMed] [Google Scholar]
  24. Zänker KS (1987) End point results of a four year adjuvant melanoma trial for stage I and II patients with 1,2-benzopyrone (abstract). Fifth International Conference in Adjuvant Therapy of Cancer. Tucson, Arizona. p 86

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES