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Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1994 Jun;120(6):354–358. doi: 10.1007/BF01247460

Inhibition of protein-kinase-C — dependent cell proliferation of human lung cancer cell lines by the dihydropyridine dexniguldipine

Hildegard M Schuller 1,, Michael Orloff 1, Gerd K Reznik 2
PMCID: PMC12201013  PMID: 8138560

Abstract

The dihydropyridine, dexniguldipine hydrochloride (B859-35), has shown therapeutic activity in experimentally induced neuroendocrine hamster lung tumors and demonstrated antiproliferative effects in a mammary cancer cell line via inhibition of Ca2+ calmodulin. Studies in NIH 3T3 fibroblasts have provided evidence that dexniguldipine may also inhibit protein kinase C (PCK). In this study, we have tested the hypothesis that dexniguldipine may inhibit the proliferation of lung cancer cells in response to autocrine or exogenous activation of PKC. Using a panel of human lung cancer cell lines, we show that dexniguldipine is a potent inhibitor of mitogenic signal transduction pathways dependent on PKC activation in several small-cell and non-small-cell lung cancer cell lines while it failed to inhibit cyclic-AMP-dependent cell proliferation.

Key words: Dexniguldipine, Lung cancer, Protein kinase C, Cell proliferation

Footnotes

Supported in part by grant R55 CA 51211-01A1 with the National Cancer Institute

References

  1. Akhtar RA, Naderi S, Abdel-Latif AA (1986) Correlative studies on the effect of carbachol onmyo-inositol triphosphate accumulation, myosin light chain phosphorylation and concentration in sphincter smooth muscle of rabbit iris. J Pharmacol Exp Ther 239:574–583 [PubMed] [Google Scholar]
  2. Anderson DJ, McKinney M (1988) Muscarinic M2 receptor-mediated cyclic AMP reduction in mechanically dissociated cortex. Brain Res 475:28–34 [DOI] [PubMed] [Google Scholar]
  3. Bunn PA Jr, Chan D, Dienhart DG, Tolley R, Tagawa M, Jewett PB (1992) Neuropeptide signal transduction in lung cancer: clinical implications of bradykinin sensitivity and overall heterogeneity. Cancer Res 52:24–31 [PubMed] [Google Scholar]
  4. Cho-Chung YS (1990) Perspectives in cancer research: role of cyclic AMP regulatory proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy. Cancer Res 50:7093–7100 [PubMed] [Google Scholar]
  5. Dahmstrup L, Rorth M, Skovgaard Paulsen H (1989) Growth factors and growth factor receptors in human malignancies, with special reference to human lung cancer Lung Cancer 5:49–68 [Google Scholar]
  6. Dumont JE, Jauniaux J-C, Roger PP (1989) The cyclic AMP-mediated stimulation of cell proliferation. Biochem Sci 14:67–71 [DOI] [PubMed] [Google Scholar]
  7. Erusalimsky JD, Friedberg I, Rozengurt E (1988) Bombesin, diacylglycerols, and phorbolesters rapidly stimulate the phosphorylation of an Mr=80,000 protein kinase C substrate in permeabilized 3T3 cells. J Biol Chem 263:19188–19194 [PubMed] [Google Scholar]
  8. Gietzen K, Bai G, Abdallah F (1990) Selective inhibition of proliferation by a novel dihydropyridine derivative with anticalmodulin activity in the mammary tumor cell line ZR75-1. Med Sci Res 18:627–629 [Google Scholar]
  9. Hughes SJ, Ashcroft SJH (1988) Effects of phorbolester and clomiphene on protein phosphorylation and insulin secretion in rat pancreatic islets. Biochem J 249:825–830 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kawamato S, Hidaka H (1984) 1-(5-Isoquinolinesulfonyl)-2-methyl-piperazine (H-7) is a selective inhibitor of protein kinase C in rabbit platelets. Biochem Biophys Res Commun 125:258–264 [DOI] [PubMed] [Google Scholar]
  11. Maenhaut YS, Roger PP, Reuse S, Dumont JE (1991) Activation of the cyclic AMP cascade as an oncogenic mechanism: the thyroid example. Biochimie 73:29–36 [DOI] [PubMed] [Google Scholar]
  12. Metzger H, Lindner E (1981) The positive inotropic-acting forskolin, a potent adenylate cyclase activator. Arzneimittelforschung 31:1248–1250 [PubMed] [Google Scholar]
  13. Orloff M, Schuller HM (1992)N-Nitrososdiethylamine (DEN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) bind to β-adrenergic receptors in hamster lung. Proc Am Assoc Cancer Res 33:120 [Google Scholar]
  14. Reznik-Schuller H (1976) Ultrastructural alterations of nonciliated cells after nitrosamine treatment and their significance for pulmonary carcinogenesis. Am J Pathol 85:549–554 [PMC free article] [PubMed] [Google Scholar]
  15. Robinson GA (1973) The biological role of cyclic AMP: un updated review. In: Kahn RA, Lands WE (eds) Prostaglandins and cyclic AMP: biological actions and clinical applications. Academic Press, New York, pp 229–247 [Google Scholar]
  16. Robinson JP, Kendall DA (1990) Niguldipine discriminates between α1-adrenergic receptor-mediated second messenger responses in rat cerebral cortex. Br J Pharmacol 100:3–4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Schuller HM (1989) Cell type specific, receptor-mediated modulation of growth kinetics in human lung cancer cell lines by nicotine and tobacco-related nitrosamines. Biochem Pharmacol 38:3439–3442 [DOI] [PubMed] [Google Scholar]
  18. Schuller HM, Cole B (1989) Regulation of cell proliferation by β-adrenergic receptors in a human adenocarcinoma cell line. Carcinogenesis 10:1753–1755 [DOI] [PubMed] [Google Scholar]
  19. Schuller HM, Becker KL, Witschi H-P (1988) An animal model for neuroendocrine lung cancer. Carcinogenesis 7:293–296 [DOI] [PubMed] [Google Scholar]
  20. Schuller HM, Witschi H-P, Nylen ES, Joshi PA, Correa E, Becker KL (1990a) Pathobiology of NNK-induced lung tumors in hamsters and the modulating effect of hyperoxia. Cancer Res 50:1960–1965 [PubMed] [Google Scholar]
  21. Schuller HM, Correa E, Orloff M, Reznik GK (1990b) Successful chemotherapy of experimental neuroendocrine lung tumors in hamsters with an antagonist of Ca2+/calmodulin, Cancer Res 50:1645–1649 [PubMed] [Google Scholar]
  22. Schuller HM, Orloff M, Reznik GK (1991) Antiproliferative effects of the Ca2+/calmodulin antagonist B859-35 and the Ca2+ channel blocker Verapamil on human lung cancer cell lines. Carcinogenesis 12:2301–2303 [DOI] [PubMed] [Google Scholar]
  23. Slaga TJ, Fisher SM, Nelson K, Gleason GL (1980) Studies on the mechanisms of skin tumor promotion: evidence for several stages in promotion. Proc Natl Acad Sci USA 77:4659–4663 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Uberall F, Maly K, Egle A, Doppler W, Hoffmann T, Grunicke HH (1991) Inhibition of cell proliferation, protein kinase C, and phorbolester-inducedfos expression by the dihydropyridine derivative B859-35. Cancer Res 51:5821–5825 [PubMed] [Google Scholar]
  25. Weinstein IB (1983) Tumour promoters, protein kinase C, phospholipid, and control of growth. Nature 302:250 [DOI] [PubMed] [Google Scholar]

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