Skip to main content
Log in

Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues

  • Original Articles
  • Intracellular Ca2+, Helenalin
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

The antitumor sesquiterpene lactone helenalin, which is found in species of the plant genusHelenium, cause a marked potentiation of the increases in intracellular free Ca2+ concentration ([Ca2+]i) produced by mitogens such as vasopressin, bradykinin, and platelet-derived growth factor in Swiss mouse 3T3 fibroblasts. Removing external Ca2+ partly attenuated the increased [Ca2+]i response. caused by helenalin. The increased [Ca2+]i responses occurred at concentrations of helenalin that inhibited cell proliferation. At higher concentrations, helenalin inhibited the [Ca2+]i responses. No change in resting [Ca2+]i was caused by helenalin even at high concentrations. Other helenalin analogues also increased the [Ca2+]i response. Helenalin did not inhibit protein kinase C (PKC) and PKC appeared to play a minor role in the effects of helenalin on [Ca2+]i responses in intact cells. Studies with saponin-permeabilized HT-29 human colon carcinosarcoma cells indicated that helenalin caused an increased accumulation of Ca2+ into nonmitochondrial stores and that the potentiating effect of helenalin on mitogen-stimulated [Ca2+]i responses was due in part to an increase in the inositol-(1,4,5)-trisphosphate-mediated release of Ca2+ from these stores.

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

Access this article

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. Allen DG, Blinks JR (1979) The interpretation of light signals from aequorin-injected skeletal and cardiac muscle cells: a new method of calibration. In: Ashley CC, Campbell AK (eds) Detection and measurement of free Ca2+ in cells. Elsevier-Holland, Amsterdam, p 159

    Google Scholar 

  2. Alley MC, Powis G, Appel PL, Kooistra KL, Lieber MM (1984) Activation and inactivation of cancer chemotherapeutic agents by rat hepatocytes cocultured with human tumor cell lines. Cancer Res 44: 549

    Google Scholar 

  3. Berridge MJ (1993) Inositol trisphosphate and calcium signaling. Nature 361: 315

    Google Scholar 

  4. Berridge MJ, Irvine RF (1989) Inositol phosphates and cell signaling. Nature 341: 197

    Google Scholar 

  5. Bird G, Burgess G, Putney J (1993) Sulfhydryl reagents and cAMP-dependent kinase increase the sensitivity of the inositol 1,4,5-trisphosphate receptor in hepatocytes. J Biol Chem 268: 17917

    Google Scholar 

  6. Bishayee S, Majumdar S, Khire J, Das M (1989) Ligand-induced dimerization of the platelet-derived growth factor receptor. J Biol Chem 264: 11699

    Google Scholar 

  7. Bootman MD, Taylor CW, Berridge MJ (1992) The thiol reagent, thimerosal, evokes Ca2+ spikes in HeLa cells by sensitizing the inositol/1,4,5-trisphosphate receptor. J Biol Chem 35: 25113

    Google Scholar 

  8. Boynton AL, Whitfield JF, Isaacs RJ, Tremblay R (1977) The control of human WI-38 cell proliferation by extracellular calcium and its elimination by SV40 virus-infected proliferative transformation. J Cell Physiol 92: 240

    Google Scholar 

  9. Carafoli E (1987) Intracellular Ca2+ homeostasis. Annu Rev Biochem 56: 395

    Google Scholar 

  10. Carpenter G, Hernandez-Sotomayor SM, Nishibe S, Todderud G, Mumby M, Wahl M (1992) Growth factor phosphorylation of PLC-gamma 1. Ciba Found Symp 164: 223

    Google Scholar 

  11. Chow SC, Powis G (1994) Mechanisms of platelet derived growth factor-induced arachidonic acid release in Swiss 3T3 fibroblasts: the role of a localized increase in free Ca2+ concentration beneath the plasma membrane and the activation of protein kinase C. Biochim Biophys Acta (in press)

  12. Fabiato A (1988) Computer programs for calculating total from specified free or free from specified total ionic concentrations in aqueous solutions containing multiple metals and ligands. Methods Enzymol 157: 378

    Google Scholar 

  13. Foster S, Duke JA (1990) A field guide to medicianal plants. Eastern and central North America. Houghton Mifflin, Boston, p 126

    Google Scholar 

  14. Gericke M, Droogmans G, Nilius B (1993) Thimerosal induced changes of intracellular calcium in human endothelial cell. Cell Calcium 14: 201

    Google Scholar 

  15. Grippo AA, Hall IH, Kiyokawa H, Muroaka O, Shen YC, Lee KH (1992) The cytotoxicity of helenalin, its mono- and difunctional esters, and related sesquiterpene lactones in murine and human tumor cells. Drug Design Discov 8: 191

    Google Scholar 

  16. Hall IH, Lee KH, Starnes CO, Sumida Y, Wu RY, Waddell TG, Cochram JW, Gerhart KG (1979) Anti-inflammatory activity of sesquiterpene lactones and related compounds. J Pharm Sci 68: 537

    Google Scholar 

  17. Hall IH, Lee KH, Starnes CO, Muraoka O, Sumida Y, Waddell TG (1980) Antihyperlipidemic activity of sesquiterpene lactones and related compounds. J Pharm Sci 69: 694

    Google Scholar 

  18. Hidaka H, Inagaki M, Kawamoto S, Sasaki Y (1984) Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry 23: 5036

    Google Scholar 

  19. Hilly M, Pietri-Rouxel F, Coquil J-F, Guy M, Mauger J-P (1993) Thiol reagents increase the affinity of the inositol 1,4,5-trisphosphate receptor. J Biol Chem 268: 16488

    Google Scholar 

  20. Hug H, Sarre TF (1993) Protein kinase C isoenzymes: divergence in signal transduction? Biochem J 291: 329

    Google Scholar 

  21. Jewell SA, Bellomo G, Thor H, Orrenius S, Smith MT (1982) Bleb formation in hepatocytes during drug metabolism is caused by disturbances in thiol and calcium ion homeostasis. Science 217: 1257

    Google Scholar 

  22. Kikkawa U, Nishizuka Y (1986) The role of protein kinase C in transmembrane signaling. Annu Rev Cell Biol 2: 149

    Google Scholar 

  23. Kumaravel G, Ashendel CL, Gandour RD (1993) Hemicholinium and related lipids: inhibitors of protein kinase C. J Med Chem 36: 177

    Google Scholar 

  24. Kupcham SM, Eakin MA, Thomas AM (1971) Tumor inhibitors. 69. Structure-cytotoxicity relationships among the sequiterpene lactones. J Med Chem 14: 1147

    Google Scholar 

  25. Lee KH, Huang ES, Piantadosi C, Pagano JS, Geissman TA (1971) Cytotoxicity of sesquiterpene lactones. Cancer Res 31: 1649

    Google Scholar 

  26. Lee KH, Furukawa H, Huang ES (1972) Antitumor agents. 3. Synthesis and cytotoxic activity of helenalin amine adducts and related derivatives. J Med Chem 15: 609

    Google Scholar 

  27. Lee KH, Hall IH, Mar EC, Starnes CO, ElGebaly SA, Waddell TG, Hadgraft RI, Ruffner CG, Weidner I (1977) Sesquiterpene antitumor agents: inhibitors of cellular metabolism. Science 196: 533

    Google Scholar 

  28. Lee KH, Ibuka T, Wu RY, Geissman TA (1977) Antimicrobial agents. 2. Structure activity relationships among sesquiterpene lactones and related compounds. Phytochemistry 16: 1177

    Google Scholar 

  29. Lee KH, Ibuka T, Sims D, Muraoka O, Kiuokawa H, Hall IH (1981) Antitumor agents. 44. Bis(helenalinyl) esters and related derivatives as novel potent antileukemic agents. J Med Chem 24: 924

    Google Scholar 

  30. Luckasen JR, White JG, Kersey JH (1974) Mitogenic properties of a calcium ionophore, A23187. Proc Natl Acad Sci USA 71: 5088

    Google Scholar 

  31. Maki M, Berezesky IK, Fargnoli J, Holbrook NJ, Trump BF (1992) Role of [Ca2+]i in induction of c-fos, c-jun and c-myc mRNA in rat PTE after oxidative stress. FASEB J 6: 919

    Google Scholar 

  32. Margolis B (1992) Protein with SH2 domains: transducers in the tyrosine kinase signaling pathway. Cell Growth Differ 3: 73

    Google Scholar 

  33. McNeil PL, McKenna MP, Taylor DC (1985) A transient rise in cytosolic calcium follows stimulation of quiescent cells with growth factors and is inhibitable with phorbol myristate acetate. J Cell Biol 101: 372

    Google Scholar 

  34. Meek DW, Street AJ (1992) Nuclear protein phosphorylation and growth control. Biochem J 287: 1

    Google Scholar 

  35. Missiaen L, Taylor CW, Berridge MJ (1991) Spontaneous calcium release from inositol trisphosphate-sensitive calcium stores. Nature 352: 241

    Google Scholar 

  36. Missiaen L, De Smedt H, Droogmans G, Casteels R (1992) Ca2+ release induced by inositol 1,4,5-trisphosphate is a steady-state phenomenon controlled by luminal Ca2+ in permeabilized cells. Nature 357: 599

    Google Scholar 

  37. Moran MF, Koch CA, Anderson D, Ellis C, England L, Martin GS, Pawson T (1990) Src homology region 2 domains direct protein-protein interactions in signal transduction. Proc Natl Acad Sci USA 87: 8622

    Google Scholar 

  38. Nishimura J, Huang JS, Deuel TF (1982) Platelet-derived growth factor stimulates tyrosine specific protein kinase activity in Swiss mouse 3T3 cell membranes. Proc Natl Acad Sci USA 79: 4303

    Google Scholar 

  39. 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 

  40. Olsen R, Seewald M, Powis G (1989) Contribution of external and internal Ca2+ to changes in intracellular free Ca2+ produced by mitogens in Swiss 3T3 fibroblasts: the role of dihydropyridine sensitive Ca2+ channels. Biochem Biophys Res Commun 162: 448

    Google Scholar 

  41. Olsen R, Seewald M, Melder DC, Berggren M, Iaizzo PA, Powis G (1991) Platelet derived growth factor blocks the increase in intracellular free Ca2+ caused by calcium ionophores and a volatile anesthetic agent in Swiss 3T3 fibroblasts without altering toxicity. Toxicol Lett 55: 117

    Google Scholar 

  42. Orrenius S, McConkey PJ, Jones PP, Nicotera P (1988) Intracellular calcium and toxicity. ISI Atlas Sci Pharmacol 6: 319

    Google Scholar 

  43. Powis G (1991) Signalling targets for anticancer drug development. Trends Pharmacol Sci 12: 188

    Google Scholar 

  44. Powis G (1992) Drugs active against growth factor and oncogene signalling pathways. The example of inhibitors ofmyo-inositol signalling. Semin Cancer Biol 3: 343

    Google Scholar 

  45. Putney JW Jr (1990) Receptor-regulated calcium entry. Pharmacol Ther 48: 427

    Google Scholar 

  46. Renard D, Seitz M, Thomas A (1992) Oxidized glutathione causes sensitization of calcium release to inositol 1,4,5-trisphosphate in permeabilized hepatocytes. Biochem J 284: 507

    Google Scholar 

  47. Rhee SG, Choi KD (1992) Regulation of inositol phospholipid-specific phospholipase C isozymes. J Biol Chem 267: 12393

    Google Scholar 

  48. Roussel MF, Shurtleff SA, Downing JR, Sherr CJ (1990) A point mutation at tyrosine-809 in the human colony-stimulating factor 1 receptor impairs mitogenesis without abrogating tyrosine kinase activity, association with phosphatidylinositol 3-kinase, or induction ofc-fos andjunB genes. Proc Natl Acad Sci USA 87: 6738

    Google Scholar 

  49. Sayers LG, Brown GR, Michell RH, Michelangeli F (1993) The effects of thimerosal on calcium uptake uptake and inositol/1,4,5-trisphosphate-induced calcium release in cerebellar microsomes. Biochem J 289: 883

    Google Scholar 

  50. Seewald MJ, Olsen RA, Powis G (1991) Release of intracellular stores of Ca2+ by polyunsaturated fatty acids and their possible role as intracellular second messengers. J Cell Pharmacol 1: 12

    Google Scholar 

  51. Smrcka AV, Hepler JR, Brown KO, Sternweis PC (1991) Regulation of polyphosphoinositide-specific phospholipase C activity by purified Gq. Science 281: 804

    Google Scholar 

  52. Steinhardt RA, Epel D (1974) Activation of sea urchin eggs by a calcium ionophore. Proc Natl Acad Sci USA 71: 1915

    Google Scholar 

  53. Taylor SJ, Chae HZ, Rhee SG, Exton JH (1991) Activation of the β1 isozyme of phospholipase C by α subunits of the Gq class of G proteins. Nature 350: 516

    Google Scholar 

  54. Tucker RW, Chang DT, Meade-Cobun K (1989) Effects of platelet-derived growth factor and fibroblast growth factor on free intracellular calcium and mitogenesis. J Cell Biochem 39: 139

    Google Scholar 

  55. Wahl MI, Oleshaw NE, Nishibe B, Rhee SG, Pledger WJ, Carpenter G (1989) Platelet-derived growth factor induces rapid and sustained tyrosine phosphorylation of phospholipase C-gamma in quiescent BALB/c 3T3 cells. Mol Cell Biol 9: 2934

    Google Scholar 

  56. Worley JF, Strobl JS (1989) Voltage-dependent calcium channels in MCF-7 human breast cancer cells and inhibition of cell growth by calcium channel antagonists. Cancer Chemother Pharmacol 24: S84

    Google Scholar 

  57. Wu D, Lee CH, Rhee SG, Simon MI (1992) Activation of phospholipase C by the α subunits of the Gq and G11 proteins in transfected Cos-7 cells. J Biol Chem 267: 1811

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Powis, G., Gallegos, A., Abraham, R.T. et al. Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues. Cancer Chemother. Pharmacol. 34, 344–350 (1994). https://doi.org/10.1007/BF00686043

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00686043

Key words

Navigation