Abstract
7-Hydroxycoumarin (7-HC) is a naturally occuring substance with a variety of biological activities, e.g. antitumoral and immunomodulatory action. the potential mechanisms of 7-HC action on tumor cells have been investigated in a model of mouse fibroblasts transformed by distinet retroviral vectors carrying the oncogenesmyc andras. Treatment of the different oncogenic transformants with 7-HC in non-cytotoxic concentrations causes a strong inhibition of their proliferative capacity as measured by growth curves. Furthermore, incubation of theras andmyc transformants with 7-HC abrogated soft agar colony formation when compared to untreated cultures. These changes in cell growth characteristics of the various oncogene-transformed mouse fibroblasts were transient, since removal of 7-HC from the cultures caused a reappearance of the transformed properties of these cells within 6 days. The 7-HC-mediated inhibition of the proliferative capacity of the transformants was preceded by a selective down-regulation of oncogene expression. These data suggest that 7-HC causes a reversible inhibition ofras- andmyc-induced neoplastic properties in transformed fibroblasts by selective down-regulation of retroviral RNA levels.
Similar content being viewed by others
Abbreviations
- 7-HC:
-
7 hydroxycoumarin
References
Chirgwin JM, Przybyla AA, MacDonald RJ, Rutter WJ (1979) Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18:5294
Clemens M, McNurlan MA (1985) Regulation of cell proliferation and differentiation by interferon. J Biochem 226:345
Colbère-Garapin F, Horodniceanu F, Kourilsky P, Garapin AC (1981) A new dominant hybrid selective marker for higher eukaryotic cells. J Mol Biol 150:1
Egan D, O'Kennedy R, Moran E, Cox D, Prosser E, Thornes RD (1990) The pharmacology, metabolism, analysis and applications of coumarin and coumarin related compounds. Drug Metab Rev 22:503–529
Einat M, Resnitzky D, Kimchi A (1985) Close link between reduction of c-myc expression by interferon and G0/G1. Nature 313:597
Ellis DW, DeFeo D, Shin TY Gondon MA, Young HA, Tshusido N, Loxy DR, Scolnick ET (1981) The p21src genes of Harvey and Kirsten sarcoma viruses originate from divergent members of a family of normal vertebrate genes. Nature 292:506
Friedman H (1981) Immunomodulating effect of cimetidine. In: Hersh EM, et al (eds) Augmenting agents in cancer therapy. Raven, New York, pp 417–425
Marshall ME, Mendelsohn L, Butler K, et al (1987) Treatment of metastatic renal cell carcinoma with coumarin (1,2-benzopyrone) and cimetidine: a pilot study. J Clin Oncol 5:862–866
Marshall ME, Rhoades JL, Mattingly C, Jennings CD (1991) Coumarin (1,2-benzopyrone) enhances DR and DQ antigen expressions by peripheral blood mononuclear cells in vitro. Mol Biother 3:204–206
Marshall ME, Albany-Jenei S, Umerani A, Zhao Q (1993) Direct cytotoxic effects of coumarin and 7-hydroxycoumarin on human malignant cell lines in vitro. J Ir Coll Physicians Surg [Suppl] 22:71
Moran E, Prosser E, Egan D, O'Kennedy R, Thornes RD (1993) The effect of coumarin and 7-hydroxycoumarin on the growth of human tumor cell lines. J Ir Coll Physicians Surg 22:41–43
Murray RDH, Mendex J, Brown SA (1982) The natural coumarins: occunence, chemistry and biochemistry Wiley, New York
Ritschel WA, Hoffmann KA (1981) Pilot study on bioavailability of coumarin and 7-hydroxycoumarin in a sustained-release dosage form. J Clin Pharmacol 21:294–300
Seliger B (1993) 7-Hydroxycoumarin mediated induction of differentiation of human malignant glioblastoma cells. J Ir Coll Physicians Surg [Suppl] 22:44–46
Seliger B, Kruppa B, Pfizenmaier K (1987) Murine gamma interferon inhibits v-mos induced fibroblast transformation via down-regulation of retroviral gene expression. J Virol 61:2567–2572
Seliger B, Kruppa G, Schäfer R, Redmond S, Pfizenmaier K (1988) IFN-gamma regulates LTR-controlled oncogene expression in transformed mouse fibroblasts at the level of mRNA transcription. J Virol 62:619
Stanton LW, Watt R, Marm KB (1983) Translocation, breakage and truncated transcripts of c-myc oncogene in murine plasmacytomas. Nature 303:401
Thornes RD, Lynch G, Sheehan MV (1982) Cimetidine and coumarin therapy of melanoma Lancet II:328
Tseng A (1993) Coumarin prevents tumorigenesis in MTV-Ha-ras transgenic animals. J Ir Coll Physicians Surg [Suppl] 22, 49–50
Tseng A, Snyder J, Lee WMF, Kirsten E (1987) Prevention of tumorigenesis of oncogene-transformed rat fibroblasts with DNA site inhibitors of poly (ADP) ribose polymerase. Proc Natl Acad Sci USA 4:1107–1111
Zänker KS (1993) Coumarins interface between cell growth inhibition, expression of oncogenes, tumor cell locomotion and cell-to-cell communication. J Ir Coll Physicians Surg [Suppl] 22:51–55
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Seliger, R., Pettersson, H. 7-Hydroxycoumarin inhibits oncogene-induced transformation of murine fibroblasts. J Cancer Res Clin Oncol 120 (Suppl 1), S23–S27 (1994). https://doi.org/10.1007/BF01377119
Issue Date:
DOI: https://doi.org/10.1007/BF01377119