Skip to main content
SpringerLink
Log in

Inhibition of growth factor binding, Ca2+ signaling and cell growth by polysulfonated azo dyes related to the antitumor agent suramin

  • Original Articles
  • Suramin, Polysulfonated Azo dyes, Growth Factor Binding
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

The ability of the polysulfonated antitumor drug suramin and six related polysulfonated azo dyes to inhibit the cell growth, platelet-derived growth factor (PDGF)-receptor binding, and intracellular Ca2+ signaling of Swiss 3T3 fibroblasts was studied. Some of the azo dyes were more potent inhibitors of PDGF binding than was suramin. The concentration giving 50% inhibition (IC50) of PDGF binding was 0.5 μm for the most potent azo dye as compared with 10 μm for suramin. The azo dyes were generally more potent inhibitors of nonmitochondrial Ca2+ uptake and of inositol(1,4,5)trisphosphate-mediated Ca2+ release in permeabilized Swiss 3T3 cells than was suramin, and they were more potent inhibitors of PDGF-induced Ca2+ signaling in intact Swiss 3T3 cells. The azo dyes were only as effective as or less effective than suramin in inhibiting the growth of Swiss 3T3 cells, with IC50 values of between 74 and 361 μm being noted for the dyes as compared with 70 μm for suramin. The difference between the growth-inhibitory activity of the azo dyes and that of suramin could not be explained by metabolism of the compounds, which was not detectable in either Swiss 3T3 cells or human liver slice preparations. The results suggest that suramin and some of the azo dyes have actions on cell growth in addition to inhibition of growth factor binding and of Ca2+ signaling.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alberts D, Miranda E, Dorr R, Nichols N, Ketcham M, MacNeal W, Hatch K, Surwit E, Childers J, Taylor C (1991) Phase II and pharmacokinetic (PK) and human tumor cloning assay (HTCA) study of suramin in advanced ovarian cancer (abstract). Proc Am Soc Clin Oncol 10:A609

    Google Scholar 

  2. Bergh J (1989) Suramin is a potent inhibitor of the cell proliferation in human non-small cell lung cancer cell lines (abstract). Proc Am Assoc Cancer Res 30:77

    Google Scholar 

  3. Berns EMJJ Schuurmans ALG, Bolt J, Lamb DJ, Foekens JA, Mulder E (1990) Antiproliferative effects of suramin on androgen responsive tumour cells. Eur J Cancer 26:470

    Google Scholar 

  4. Betsholtz C, Johnsson A, Heldin CK, Westermark B (1986) Efficient reversion of simian sarcoma virus transformation and inhibition of growth-factor induced mitogenesis by suramin (abstract). Proc Natl Acad Sci USA 83:6440

    Google Scholar 

  5. Bootman MD, Pay GF, Rick CE, Tones MA (1990) Two sulphonated dye compounds which compete for inositol 1,4,5-trisphosphate binding to rat liver microsomes: effects on 5′-phosphatase activity. Biochem Biophys Res Commun 166:1334

    Google Scholar 

  6. Bowen-Pope DF, Ross R (1985) Methods for studying the platelet-derived growth factor receptor. Methods Enzymol 109:69

    Google Scholar 

  7. Chapman DE, Moore TJ, Michener SR, Powis G (1990) Metabolism and covalent binding of [14C]toluene by human and rat liver microsomal fractions and liver slices. Drug Metab Dispos 18:929

    Google Scholar 

  8. Chen Y, Rabinovitch PS (1989) Platelet-derived growth factor, epidermal growth factor, and insulin-like growth factor I regulate specific cell-cycle parameters of human diploid fibroblasts in serum-free culture. J Cell Physiol 140:59

    Google Scholar 

  9. Cheson D, Levine AM, Mildvan D (1987) Suramin therapy in AIDS and related disorders. JAMA 248:1347

    Google Scholar 

  10. Clark J, Chu M, Calabresi P (1989) Growth inhibition of colon cancer cells by genutein and suramin (abstract). Proc Am Assoc Cancer Res 30:557

    Google Scholar 

  11. Coffey RJ Jr, Leof EB, Shipley GD, Moses HL (1987) Suramin inhibition of growth factor receptor binding and mitogenicity in AKR-2B cells. J Cell Physiol 132:143

    Google Scholar 

  12. Danesi R, La Rocca R, Stein C, Neckers L, Myers C (1989) Effect of suramin on the human glioma cell line U706T (abstract). Proc Am Assoc Cancer Res 30:578

    Google Scholar 

  13. De Clercq E (1979) Suramin: a potent inhibitor of the reverse transcriptase of RNA tumor viruses. Cancer Lett 8:9

    Google Scholar 

  14. Eisenberger M, Jodrell D, Sinibaldi V, Zuhowski E, Jacobs S, Egorin M, Van Echo DA (1991) Preliminary evidence of antitumor activity against prostate cancer (PRCA) observed in a phase I trial with suramin (abstract). Proc Am Soc Clin Oncol 10:A537

    Google Scholar 

  15. Fantini J, Guo X-J, Marvaldi J, Rougon G (1990) Suramin inhibits proliferation of rat glioma cells and alters N-CAM cell surface expression. Int J Cancer 45:554

    Google Scholar 

  16. Food and Drug Administration (1987) Annual report, suramin. FDA, Washington, D. C.

    Google Scholar 

  17. Gill DL, Cheuh SH (1985) An intracellular (ATP+Mg2+)-dependent calcium pump within the N1E-115 neuronal cell line. J Biol Chem 160:9289

    Google Scholar 

  18. Heldin C-H, Westermark B (1990) Platelet-derived growth factor: mechanism of action and possible in vivo function. Cell Regul 1:555

    Google Scholar 

  19. Hesketh TR, Morris JDH, Moore JP, Metcalfe JC (1988) Ca2+ and pH responses to sequential additions of mitogens in single 3T3 fibroblasts: correlations with DNA synthesis. J Biol Chem 263: 11879

    Google Scholar 

  20. Hosang M (1985) Suramin binds to PDGF and inhibits its biological activity. J Cell Biochem 29:265

    Google Scholar 

  21. Iversen J, Scher H, Motzer R, Forrest A, Curley T, Tong W, Niedzwiecki D (1991) Suramin (SUR): impact of individualized pharmacokinetic (PK) dosing on outcome in patients with prostatic cancer (PC) and renal cell carcinoma (RCC) (abstract). Proc 10:A283

    Google Scholar 

  22. Jacquemin-Sablon A (1991) Suramin is an inhibitor of DNA topoisomerase II (abstract). Proc Am Assoc Cancer Res 32:A2008

    Google Scholar 

  23. Jindal HK, Anderson CW, Davis RG, Vishwanatha JK (1990) Suramin affects DNA synthesis in HeLa cells by inhibition of DNA polymerases. Cancer Res 50:7754

    Google Scholar 

  24. Kielian MC, Steinman RM, Cohn ZA (1982) Intralysosomal accumulation of polyanions: I. Fusion of pinocytic and phagocytic vacuoles with secondary lysosomes. J Cell Biol 93:866

    Google Scholar 

  25. Kriz R, Lin L-L, Sultzman L, Ellis C, Heldin C-H, Pawson T, Knopf J (1990) Phospholipase C isozymes: structural and functional similarities. In: Wolstenholme G.E.W. (eds) Proto-oncogenes in cell development, Ciba Foundation symposium. Wiley, Chichester, pp 112–127

    Google Scholar 

  26. La Rocca RV, Myers CE, Stein CA, Cooper MR, Uhrich M (1990) Effect of suramin in patients with refractory nodular lymphomas requiring systemic therapy (abstract). Proc Am Soc Clin Oncol 9:A1041

    Google Scholar 

  27. La Rocca RV, Stein CA, Myers CE (1990) Suramin: prototype of a new generation of antitumor compounds. Cancer Cells 2:106

    Google Scholar 

  28. Levine A, Gill P, Cohen J, Hawkins JG, Formenti SC, Aguilai S, Meyer PR, Krailo M, Parke J, Rasheed S (1986) Suramin antiviral therapy in the acquired immunodeficiency syndrome. Ann Intern Med 105:32

    Google Scholar 

  29. Levine WG (1991) Metabolism of azo dyes: implication for detoxification and activatin. Drug Metab Rev 23:253

    Google Scholar 

  30. Mahoney CW, Azzi A, Huang KP (1990) Effects of suramin, an anti-human immunodeficiency virus reverse transcriptase agent, on protein kinase C. Differential activation and inhibition of protein kinase C isozymes. J Biol Chem 265:5424

    Google Scholar 

  31. Majerus PW, Ross TS, Cunningham TW, Caldwell KK, Jefferson AB, Bansal VS (1990) Recent insights in phosphatidylinositol signaling. Cell 63:459

    Google Scholar 

  32. Mills G, Zhang N, May C, Hill M, Chung A (1990) Suramin prevents binding of interleukin 2 to its cell surface receptor: a possible mechanism for immunosuppression. Cancer Res 50:3036

    Google Scholar 

  33. Mitsuya M, Popovic M, Yarchoan R, Matsushita S, Gallo RC, Broder S (1984) Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV III. Science 226:172

    Google Scholar 

  34. Myers CE, Chabner BA (1990) Anthracyclines in cancer chemotherapy: principles and practice. J. B. Lippincott, Philadelphia

    Google Scholar 

  35. Olsen R, Santone K, Melder D, Oakes SG, Abraham R, Powis G (1988) An increase in intracellular free Ca2+ associated with serum free growth stimulation of Swiss 3T3 fibroblasts by epidermal growth factor in the presence of bradykinin. J Biol Chem 263:18030

    Google Scholar 

  36. Pollak M, Richard M (1990) Suramin blockade of insulin-like growth factor 1-stimulated proliferation of human osteosarcoma cells. J Natl Cancer Inst 82:1349

    Google Scholar 

  37. Powis G, Lee-See K, Santone KS, Melder DC, Hodnett EM (1987) Quinoneimines as substrates for quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase] and the effect of dicumarol on their cytotoxicity. Biochem Pharmacol 36:2473

    Google Scholar 

  38. Powis G, Lowry S, Forrai L, Secrist P, Abraham R (1991) Inhibition of phosphoinositide phospholipase C by compounds U-73 122 and D-609. J Cell Pharmacol 2:257

    Google Scholar 

  39. Regelson W (1968) The antimitotic activity of polyanions. Adv Chemother 3:303

    Google Scholar 

  40. Roffo AH, Calcagno O (1930) Estudio del rojo neutro y sus sales sobre et desarrollo de la cultivos in vitro (in spanish). Bol Inst Med Estud Trat Cancer Univ Buenos Aires 7:29

    Google Scholar 

  41. Ruprecht RM, Lorsch J, Trites DH (1986) Analysis of suramin plasma levels by ion-pair high-performance liquid chromatography under isocratic conditions. J Chromatogr 378:498

    Google Scholar 

  42. Seewald MJ, Olsen RA, Powis G (1989) Suramin blocks intracellular Ca2+ release and growth factor-induced increases in cytoplasmic free Ca2+ concentration. Cancer Lett 49:107

    Google Scholar 

  43. Seewald MJ, Schlager JJ, Olsen RA, Melder DC, Powis G (1989) High molecular weight dextran sulfate inhibits intracellular Ca2+ release and decreases growth factor-induced increases in intracellular free Ca2+ in Swiss 3T3 fibroblasts. cancer Commun 3:151

    Google Scholar 

  44. Sjölund M, Thyberg J (1989) Suramin inhibits binding and degradation of platelet-derived growth factor in arterial smooth muscle cells but does not interfere with autocrine stimulation of DNA synthesis. Cell Tissue Res 256:35

    Google Scholar 

  45. Snedecor GW, Cochran WG (1967) The comparison of two samples. In: Statistical methods. Ames, Iowa; Iowa State University, pp 91

    Google Scholar 

  46. Spigelman Z, Dowers A, Kennedy S, diSorbo D, O'Brien MO, Barr R, McCaffrey R (1987) Antiproliferative effects of suramin on lymphoid cells. Cancer Res 47:4694

    Google Scholar 

  47. Stein CA, La Rocca RV, Thomas R, McAtee N, Myers CE (1989) Suramin: an anticancer drug with a unique mechanism of action. J Clin Oncol 7:499

    Google Scholar 

  48. Stein CA, Zhang X, La Rocca R, Myers CE, Neckers LM (1989) Suramin causes inhibition of HL-60 transferrin receptor expression and cell growth and stimulates partial cellular differentiation (abstract). Proc Am Assoc Cancer Res 30:80

    Google Scholar 

  49. Sugiura K, Benedict SR (1929) The action of certain dyestuffs on the growth of transplantable tumors. J Cancer Res Clin Oncol 13:340

    Google Scholar 

  50. Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61:203

    Google Scholar 

  51. Van Oosterom AT, De Smedt EA, Denis LJ, Bruijn EA de, Mahler C (1990) Suramin for prostatic cancer: a phase I/II study in advanced extensively pretreated disease. Eur J Cancer 26:422

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Arizona Cancer Center, Arizona Health Sciences Center, 1501 N. Campbell Avenue, 85724, Tucson, AZ, USA

    G. Powis, M. J. Seewald, D. Melder, M. Hoke, C. Gratas, T. A. Christensen & D. E. Chapman

Authors
  1. G. Powis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. J. Seewald
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Melder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Hoke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Gratas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. A. Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. E. Chapman
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported by NIH grant CA 42286

Rights and permissions

Reprints and permissions

About this article

Cite this article

Powis, G., Seewald, M.J., Melder, D. et al. Inhibition of growth factor binding, Ca2+ signaling and cell growth by polysulfonated azo dyes related to the antitumor agent suramin. Cancer Chemother. Pharmacol. 31, 223–228 (1992). https://doi.org/10.1007/BF00685552

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00685552

Keywords

Search

Navigation