Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1995 Aug;72(2):287–292. doi: 10.1038/bjc.1995.326

Reversal of radiation-induced cisplatin resistance in murine fibrosarcoma cells by selective modulation of the cyclic GMP-dependent transduction pathway.

H Eichholtz-Wirth 1
PMCID: PMC2033992  PMID: 7640207

Abstract

Cisplatin resistance, induced in murine fibrosarcoma cells (SSK) in vitro or in vivo by low-dose irradiation, can be overcome by activation of the cyclic GMP(cGMP)-dependent transduction pathway. This is mediated either by stimulating cGMP formation with sodium nitroprusside or by replacing cGMP with a selective activator of the cGMP-dependent protein kinase, 8-bromo-cGMP. The cyclic AMP-dependent transduction pathway is not involved in cisplatin resistance. Instead, activation of cAMP sensitises both parental and resistant SSK cells equally to the action of cisplatin. There is a 1.8 to 2.5-fold increase in drug toxicity, depending on the activating agent. Enhancement of cisplatin sensitivity is induced by specific inhibition of cAMP hydrolysis, increase in cAMP formation or by increasing the activation potential to cAMP-dependent protein kinase by specific cAMP analogues. Cells that have lost cisplatin resistance respond to cGMP- or cAMP-elevating agents in the same way as the parental SSK cells. The radiation sensitivity is unchanged in all cell lines, even after activation of cAMP or cGMP. These results suggest that specific DNA repair pathways are altered by radiation but affected only in cisplatin damage repair, which is regulated by cGMP. Although there is ample cooperativity and interaction between the cAMP- and the cGMP-dependent transduction pathways, specific substrate binding by cGMP appears to play an important role in radiation-induced cisplatin resistance.

Full text

PDF
287

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abraham I., Hunter R. J., Sampson K. E., Smith S., Gottesman M. M., Mayo J. K. Cyclic AMP-dependent protein kinase regulates sensitivity of cells to multiple drugs. Mol Cell Biol. 1987 Sep;7(9):3098–3106. doi: 10.1128/mcb.7.9.3098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ally S., Tortora G., Clair T., Grieco D., Merlo G., Katsaros D., Ogreid D., Døskeland S. O., Jahnsen T., Cho-Chung Y. S. Selective modulation of protein kinase isozymes by the site-selective analog 8-chloroadenosine 3',5'-cyclic monophosphate provides a biological means for control of human colon cancer cell growth. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6319–6322. doi: 10.1073/pnas.85.17.6319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Basu A., Lazo J. S. Sensitization of human cervical carcinoma cells to cis-diamminedichloroplatinum(II) by bryostatin 1. Cancer Res. 1992 Jun 1;52(11):3119–3124. [PubMed] [Google Scholar]
  4. Beavo J. A., Reifsnyder D. H. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci. 1990 Apr;11(4):150–155. doi: 10.1016/0165-6147(90)90066-H. [DOI] [PubMed] [Google Scholar]
  5. Butt E., Nolte C., Schulz S., Beltman J., Beavo J. A., Jastorff B., Walter U. Analysis of the functional role of cGMP-dependent protein kinase in intact human platelets using a specific activator 8-para-chlorophenylthio-cGMP. Biochem Pharmacol. 1992 Jun 23;43(12):2591–2600. doi: 10.1016/0006-2952(92)90148-c. [DOI] [PubMed] [Google Scholar]
  6. Chao C. C., Huang S. L., Lee L. Y., Lin-Chao S. Identification of inducible damage-recognition proteins that are overexpressed in HeLa cells resistant to cis-diamminedichloroplatinum (II). Biochem J. 1991 Aug 1;277(Pt 3):875–878. doi: 10.1042/bj2770875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cho-Chung Y. S. Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy. Cancer Res. 1990 Nov 15;50(22):7093–7100. [PubMed] [Google Scholar]
  8. Christen R. D., Jekunen A. P., Jones J. A., Thiebaut F., Shalinsky D. R., Howell S. B. In vitro modulation of cisplatin accumulation in human ovarian carcinoma cells by pharmacologic alteration of microtubules. J Clin Invest. 1993 Jul;92(1):431–440. doi: 10.1172/JCI116585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Connolly B. J., Willits P. B., Warrington B. H., Murray K. J. 8-(4-Chlorophenyl)thio-cyclic AMP is a potent inhibitor of the cyclic GMP-specific phosphodiesterase (PDE VA). Biochem Pharmacol. 1992 Dec 15;44(12):2303–2306. doi: 10.1016/0006-2952(92)90673-7. [DOI] [PubMed] [Google Scholar]
  10. Eichholtz-Wirth H., Hietel B. Cisplatin resistance in mouse fibrosarcoma cells after low-dose irradiation in vitro and in vivo. Br J Cancer. 1994 Oct;70(4):579–584. doi: 10.1038/bjc.1994.354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eichholtz-Wirth H., Reidel G., Hietel B. Radiation-induced transient cisplatin resistance in murine fibrosarcoma cells associated with elevated metallothionein content. Br J Cancer. 1993 May;67(5):1001–1006. doi: 10.1038/bjc.1993.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Francis S. H., Corbin J. D. Structure and function of cyclic nucleotide-dependent protein kinases. Annu Rev Physiol. 1994;56:237–272. doi: 10.1146/annurev.ph.56.030194.001321. [DOI] [PubMed] [Google Scholar]
  13. Geiger J., Nolte C., Butt E., Sage S. O., Walter U. Role of cGMP and cGMP-dependent protein kinase in nitrovasodilator inhibition of agonist-evoked calcium elevation in human platelets. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1031–1035. doi: 10.1073/pnas.89.3.1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hall I. P., Widdop S., Townsend P., Daykin K. Control of cyclic AMP levels in primary cultures of human tracheal smooth muscle cells. Br J Pharmacol. 1992 Oct;107(2):422–428. doi: 10.1111/j.1476-5381.1992.tb12762.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hallahan D. E., Virudachalam S., Schwartz J. L., Panje N., Mustafi R., Weichselbaum R. R. Inhibition of protein kinases sensitizes human tumor cells to ionizing radiation. Radiat Res. 1992 Mar;129(3):345–350. [PubMed] [Google Scholar]
  16. Hofmann F., Dostmann W., Keilbach A., Landgraf W., Ruth P. Structure and physiological role of cGMP-dependent protein kinase. Biochim Biophys Acta. 1992 Apr 30;1135(1):51–60. doi: 10.1016/0167-4889(92)90165-8. [DOI] [PubMed] [Google Scholar]
  17. Hughes E. N., Engelsberg B. N., Billings P. C. Purification of nuclear proteins that bind to cisplatin-damaged DNA. Identity with high mobility group proteins 1 and 2. J Biol Chem. 1992 Jul 5;267(19):13520–13527. [PubMed] [Google Scholar]
  18. Isonishi S., Andrews P. A., Howell S. B. Increased sensitivity to cis-diamminedichloroplatinum(II) in human ovarian carcinoma cells in response to treatment with 12-O-tetradecanoylphorbol 13-acetate. J Biol Chem. 1990 Mar 5;265(7):3623–3627. [PubMed] [Google Scholar]
  19. Jacobowitz O., Chen J., Premont R. T., Iyengar R. Stimulation of specific types of Gs-stimulated adenylyl cyclases by phorbol ester treatment. J Biol Chem. 1993 Feb 25;268(6):3829–3832. [PubMed] [Google Scholar]
  20. Jiang H., Colbran J. L., Francis S. H., Corbin J. D. Direct evidence for cross-activation of cGMP-dependent protein kinase by cAMP in pig coronary arteries. J Biol Chem. 1992 Jan 15;267(2):1015–1019. [PubMed] [Google Scholar]
  21. Karin M. Signal transduction from the cell surface to the nucleus through the phosphorylation of transcription factors. Curr Opin Cell Biol. 1994 Jun;6(3):415–424. doi: 10.1016/0955-0674(94)90035-3. [DOI] [PubMed] [Google Scholar]
  22. Lange-Carter C. A., Vuillequez J. J., Malkinson A. M. 8-Chloroadenosine mediates 8-chloro-cyclic AMP-induced down-regulation of cyclic AMP-dependent protein kinase in normal and neoplastic mouse lung epithelial cells by a cyclic AMP-independent mechanism. Cancer Res. 1993 Jan 15;53(2):393–400. [PubMed] [Google Scholar]
  23. Lincoln T. M., Cornwell T. L. Intracellular cyclic GMP receptor proteins. FASEB J. 1993 Feb 1;7(2):328–338. doi: 10.1096/fasebj.7.2.7680013. [DOI] [PubMed] [Google Scholar]
  24. Lincoln T. M., Keely S. L. Regulation of cardiac cyclic GMP-dependent protein kinase. Biochim Biophys Acta. 1981 Aug 17;676(2):230–244. doi: 10.1016/0304-4165(81)90192-6. [DOI] [PubMed] [Google Scholar]
  25. Mann S. C., Andrews P. A., Howell S. B. Modulation of cis-diamminedichloroplatinum(II) accumulation and sensitivity by forskolin and 3-isobutyl-1-methylxanthine in sensitive and resistant human ovarian carcinoma cells. Int J Cancer. 1991 Jul 30;48(6):866–872. doi: 10.1002/ijc.2910480613. [DOI] [PubMed] [Google Scholar]
  26. Nishio K., Morikage T., Kubota N., Ohmori T., Takeda Y., Fujiwara Y., Miki K., Abe K., Saijo N. Alteration of type II regulatory subunit of cAMP-dependent protein kinase in human cisplatin-resistant cells as a basis of collateral sensitivity to 8-chloro-cAMP. Jpn J Cancer Res. 1992 Jul;83(7):754–760. doi: 10.1111/j.1349-7006.1992.tb01976.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ogreid D., Ekanger R., Suva R. H., Miller J. P., Døskeland S. O. Comparison of the two classes of binding sites (A and B) of type I and type II cyclic-AMP-dependent protein kinases by using cyclic nucleotide analogs. Eur J Biochem. 1989 Apr 15;181(1):19–31. doi: 10.1111/j.1432-1033.1989.tb14689.x. [DOI] [PubMed] [Google Scholar]
  28. Rohlff C., Clair T., Cho-Chung Y. S. 8-Cl-cAMP induces truncation and down-regulation of the RI alpha subunit and up-regulation of the RII beta subunit of cAMP-dependent protein kinase leading to type II holoenzyme-dependent growth inhibition and differentiation of HL-60 leukemia cells. J Biol Chem. 1993 Mar 15;268(8):5774–5782. [PubMed] [Google Scholar]
  29. Rohlff C., Safa B., Rahman A., Cho-Chung Y. S., Klecker R. W., Glazer R. I. Reversal of resistance to adriamycin by 8-chloro-cyclic AMP in adriamycin-resistant HL-60 leukemia cells is associated with reduction of type I cyclic AMP-dependent protein kinase and cyclic AMP response element-binding protein DNA-binding activities. Mol Pharmacol. 1993 Mar;43(3):372–379. [PubMed] [Google Scholar]
  30. Rubin E., Kharbanda S., Gunji H., Weichselbaum R., Kufe D. cis-Diamminedichloroplatinum(II) induces c-jun expression in human myeloid leukemia cells: potential involvement of a protein kinase C-dependent signaling pathway. Cancer Res. 1992 Feb 15;52(4):878–882. [PubMed] [Google Scholar]
  31. Sandberg M., Butt E., Nolte C., Fischer L., Halbrügge M., Beltman J., Jahnsen T., Genieser H. G., Jastorff B., Walter U. Characterization of Sp-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole- 3',5'-monophosphorothioate (Sp-5,6-DCl-cBiMPS) as a potent and specific activator of cyclic-AMP-dependent protein kinase in cell extracts and intact cells. Biochem J. 1991 Oct 15;279(Pt 2):521–527. doi: 10.1042/bj2790521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sekhar K. R., Hatchett R. J., Shabb J. B., Wolfe L., Francis S. H., Wells J. N., Jastorff B., Butt E., Chakinala M. M., Corbin J. D. Relaxation of pig coronary arteries by new and potent cGMP analogs that selectively activate type I alpha, compared with type I beta, cGMP-dependent protein kinase. Mol Pharmacol. 1992 Jul;42(1):103–108. [PubMed] [Google Scholar]
  33. Souness J. E., Diocee B. K., Martin W., Moodie S. A. Pig aortic endothelial-cell cyclic nucleotide phosphodiesterases. Use of phosphodiesterase inhibitors to evaluate their roles in regulating cyclic nucleotide levels in intact cells. Biochem J. 1990 Feb 15;266(1):127–132. doi: 10.1042/bj2660127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Van Lookeren Campagne M. M., Villalba Díaz F., Jastorff B., Kessin R. H. 8-Chloroadenosine 3',5'-monophosphate inhibits the growth of Chinese hamster ovary and Molt-4 cells through its adenosine metabolite. Cancer Res. 1991 Mar 15;51(6):1600–1605. [PubMed] [Google Scholar]
  35. Walton G. M., Spiess J., Gill G. N. Phosphorylation of high mobility group 14 protein by cyclic nucleotide-dependent protein kinases. J Biol Chem. 1982 Apr 25;257(8):4661–4668. [PubMed] [Google Scholar]
  36. Wilson R. E., Taylor S. L., Atherton G. T., Johnston D., Waters C. M., Norton J. D. Early response gene signalling cascades activated by ionising radiation in primary human B cells. Oncogene. 1993 Dec;8(12):3229–3237. [PubMed] [Google Scholar]
  37. Yoshimura M., Cooper D. M. Type-specific stimulation of adenylylcyclase by protein kinase C. J Biol Chem. 1993 Mar 5;268(7):4604–4607. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES