Skip to main content

Advertisement

SpringerLink
Log in

Verapamil Inhibits L-type Calcium Channel Mediated Apoptosis in Human Colon Cancer Cells

  • Original Contribution
  • Published:
Diseases of the Colon & Rectum

Abstract

Purpose

Treatment with calcium channel blockers have been associated with increased colon cancer mortality in epidemiologic studies. We examined the potential expression and function of calcium channels in two human colon cancer cell lines.

Methods

Both primary (collected at operation) and commercially-available human colon cancer cell lines were used. The colon cancer cells were incubated with a calcium channel blocker (verapamil) and a calcium channel agonist (BayK 8644) at clinically relevant concentrations. L-type calcium channel mRNA was determined by reverse-transcription polymerase chain reaction. Intracellular calcium ion levels were measured with fluorometry and apoptosis with flow cytometry.

Results

Both types of cells expressed L-type calcium channel mRNA, comprising an alpha-1D and a beta-3 subunit, whereas the cells were negative for N-type and P-type channels. The selective calcium channel agonist (BayK 8644), dose-dependently increased intracellular calcium ion levels and the level of apoptosis in primary human colon cancer cells. Pretreatment with verapamil completely abolished both calcium channel agonist-induced influx of calcium and apoptosis in these cells.

Conclusions

These data demonstrate that human colon cancer cells express L-type calcium channels that mediate calcium influx and apoptosis, which warrants further studies to determine whether calcium channel blockers may promote colon cancer growth.

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

FIGURE 1
FIGURE 2
FIGURE 3
FIGURE 4
FIGURE 5

Similar content being viewed by others

References

  1. Pahor M, Guralnik JM, Ferrucci L, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet 1996;348:493–7.

    Article  PubMed  CAS  Google Scholar 

  2. Pahor M, Manto A, Pedone C, Carosella L, Guralnik JM, Carbonin P. Age and severe adverse drug reactions caused by nifedipine and verapamil. Gruppo Italiano di Farmacovigilanza nell’ Anziano (GIFA). J Clin Epidemiol 1996;49:921–8.

    Article  PubMed  CAS  Google Scholar 

  3. Furberg CD, Pahor M, Psaty BM. The unnecessary controversy. Eur Heart J 1996;17:1142–7.

    PubMed  CAS  Google Scholar 

  4. Hardell L, Axelson O, Fredrikson M. Antihypertensive drugs and risk of malignant diseases. Lancet 1996;348:542.

    Article  PubMed  CAS  Google Scholar 

  5. Lindholm LH, Anderson H, Ekbom T, et al. Relation between drug treatment and cancer in hypertensives in the Swedish trial in old patients with hypertension 2: a 5-year, prospective, randomized, controlled trial. Lancet 2001;358:539–44.

    Article  PubMed  CAS  Google Scholar 

  6. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97.

    Article  Google Scholar 

  7. Whitfield JF. Calcium signals and cancer. Crit Rev Oncol 1992;3:55–90.

    CAS  Google Scholar 

  8. Berridge MJ, Bootman MD, Lipp P. Calcium—a life and death signal. Nature 1998;395:645–8.

    Article  PubMed  CAS  Google Scholar 

  9. Bootman MD, Collins TJ, Peppiatt CM, et al. Calcium signaling—an overview. Semin Cell Dev Biol 2001;12:3–10.

    Article  PubMed  CAS  Google Scholar 

  10. Striessnig J. Pharmacology, structure and function of cardiac L-type Ca(2+) channels. Cell Physiol Biochem 1999;9:242–69.

    Article  PubMed  CAS  Google Scholar 

  11. Perez-Reyes E, Schneider T. Molecular biology of calcium channels. Kidney Int 1995;48:1111–24.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang L, Zhou W, Velculescu VE, et al. Gene expression profiles in normal and cancer cells. Science 1997;276:1268–72.

    Article  PubMed  CAS  Google Scholar 

  13. Wang XT, Nagaba Y, Cross HS, Wrba F, Zhang L, Guggino SE. The mRNA of L-type calcium channel elevated in colon cancer: protein distribution in normal and cancerous colon. Am J Pathol 2000;157:1549–62.

    PubMed  CAS  Google Scholar 

  14. Opie LH, Buhler FR, Fleckenstein A, et al. International society and federation of cardiology: working group on classification of calcium antagonists for cardiovascular disease. Am J Cardiol 1987;60:630–2.

    Article  PubMed  CAS  Google Scholar 

  15. Jones SW. Overview of voltage-dependent calcium channels. J Bioenerg Biomembr 1998;30:299–312.

    Article  PubMed  CAS  Google Scholar 

  16. Baten A, Sakamoto K, Shamsuddin AM. Long-term culture of normal human colonic epithelial cells in vitro. FASEB J 1992;6:2726–34.

    PubMed  CAS  Google Scholar 

  17. Corps AN, Brown KD. Stimulation of intestinal epithelial cell proliferation in culture by growth factors in human and ruminant mammary secretions. J Endocrinol 1987;113:285–90.

    Article  PubMed  CAS  Google Scholar 

  18. Conteas CN, McMorrow B, Luk GD. Modulation of epidermal growth factor-induced cell proliferation and receptor binding by insulin in cultured intestinal epithelial cells. Biochem Biophys Res Commun 1989;161:414–9.

    Article  PubMed  CAS  Google Scholar 

  19. Pandis N, Heim S, Bardi G, Limon J, Mandahl N, Mitelman F. Improved technique for short-term culture and cytogenetic analysis of human breast cancer. Genes Chromosomes Cancer 1992;5:14–20.

    Article  PubMed  CAS  Google Scholar 

  20. Evans GS, Flint N, Potten CS. Primary cultures for studies of cell regulation and physiology in intestinal epithelium. Annu Rev Physiol 1994;56:399–417.

    Article  PubMed  CAS  Google Scholar 

  21. Barry EL. Expression of mRNAs for the alpha 1 subunit of voltage-gated calcium channels in human osteoblast-like cell lines and in normal human osteoblasts. Calcif Tissue Int 2000;66:145–50.

    Article  PubMed  CAS  Google Scholar 

  22. Sheppard BJ, Williams M, Plummer HK, Schuller HM. Activation of voltage-operated Ca2 + channels in human small cell lung carcinoma by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Int J Oncol 2000;16:513–8.

    PubMed  CAS  Google Scholar 

  23. Koopman G, Reutelingsperger CP, Kuijten GA, Keehnen RM, Pals ST, van Oers MH. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 1994;84:1415–20.

    PubMed  CAS  Google Scholar 

  24. van Engeland M, Ramaekers FC, Schutte B, Reutelingsperger CP. A novel assay to measure loss of plasma membrane asymmetry during apoptosis of adherent cells in culture. Cytometry 1996;24:131–9.

    Article  PubMed  Google Scholar 

  25. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J. International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev 2005;57:411–25.

    Article  PubMed  CAS  Google Scholar 

  26. Wargovich MJ, Lointier PH. Calcium and vitamin D modulate mouse colon epithelial proliferation and growth characteristics of a human colon tumor cell line. Can J Physiol Pharmacol 1987;65:472–7.

    PubMed  CAS  Google Scholar 

  27. Trump BF, Berezesky IK. Calcium-mediated cell injury and cell death. FASEB J 1995;9:219–28.

    PubMed  CAS  Google Scholar 

  28. Adell-Carceller R, Segarra-Soria M, Gibert-Jerez J, et al. Inhibitory effect of calcium on carcinogenesis at the site of colonic anastomosis: an experimental study. Dis Colon Rectum 1997;40:1376–81.

    Article  PubMed  CAS  Google Scholar 

  29. Kallay E, Bajna E, Wrba F, Kriwanek S, Peterlik M, Cross HS. Dietary calcium and growth modulation of human colon cancer cells: role of the extracellular calcium-sensing receptor. Cancer Detect Prev 2000;24:127–36.

    PubMed  CAS  Google Scholar 

  30. Jarvinen R, Knekt P, Hakulinen T, Aromaa A. Prospective study on milk products, calcium and cancers of the colon and rectum. Eur J Clin Nutr 2001;55:1000–7.

    Article  PubMed  CAS  Google Scholar 

  31. Wu K, Willett WC, Fuchs CS, Colditz GA, Giovannucci EL. Calcium intake and risk of colon cancer in women and men. J Natl Cancer Inst 2002;94:437–46.

    PubMed  Google Scholar 

  32. Carroll KK. Dietary fats and cancer. Am J Clin Nutr 1996;53:S1064–7.

    Google Scholar 

  33. Wargovich MJ. Fish oil and colon cancer. Gastroenterology 1992;103:1096–8.

    PubMed  CAS  Google Scholar 

  34. Rose DP, Connolly JM. Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther 1999;83:217–44.

    Article  PubMed  CAS  Google Scholar 

  35. DeCoursey TE. Mechanism of K+ channel block by verapamil and related compounds in rat alveolar epithelial cells. J Gen Physiol 1995;106:745–79.

    Article  PubMed  CAS  Google Scholar 

  36. DeCoursey TE, Chandy KG, Gupta S, Cahalan MD. Voltage-dependent ion channels in T-lymphocytes. J Neuroimmunol 1985;10:71–95.

    Article  PubMed  CAS  Google Scholar 

  37. Jonas M, Goldbourt U, Boyko V, Mandelzweig L, Behar S, Reicher-Reiss H. Nifedipine and cancer mortality: ten-year follow-up of 2607 patients after acute myocardial infarction. Cardiovasc Drugs Ther 1998;12:177–81.

    Article  PubMed  CAS  Google Scholar 

  38. Michels KB, Rosner BA, Walker AM, et al. Calcium channel blockers, cancer incidence, and cancer mortality in a cohort of U.S. women: the nurses’ health study. Cancer 1998;83:2003–7.

    Article  PubMed  CAS  Google Scholar 

  39. Kanamasa K, Kimura A, Miyataka M, Takenaka T, Ishikawa K. Incidence of cancer in postmyocardial infarction patients treated with short-acting nifedipine and diltiazem. Secondary Prevention Group. Cancer 1999;85:1369–74.

    Article  PubMed  CAS  Google Scholar 

  40. Sajadieh A, Storm HH, Hansen JF. Verapamil and risk of cancer in patients with coronary artery disease. DAVIT Study Group. Danish Verapamil Infarction Trial. Am J Cardiol 1999;83:1419–22.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Malmö University Hospital, Lund University, SE-20502, Malmö, Sweden

    Antoni Zawadzki M.D., Qing Liu Ph.D., Yusheng Wang Ph.D., Bengt Jeppsson M.D., Ph.D. & Henrik Thorlacius M.D., Ph.D.

  2. Department of Community Medicine, Malmö University Hospital, Lund University, Malmö, Sweden

    Arne Melander M.D., Ph.D.

  3. NEPI Foundation, Malmö University Hospital, Lund University, Malmö, Sweden

    Arne Melander M.D., Ph.D.

Authors
  1. Antoni Zawadzki M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qing Liu Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yusheng Wang Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arne Melander M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bengt Jeppsson M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Henrik Thorlacius M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Henrik Thorlacius M.D., Ph.D..

Additional information

This work was supported by the Swedish Medical Research Council (2006–4889), Crafoord Foundation, Einar and Inga Nilsson Foundation, Greta and Johan Kock Foundation, Fröken Agnes Nilsson Foundation, Nanna Svartz Foundation, Ruth and Richard Julin Foundation, MAS Foundation against cancer, The NEPI Foundation, and Lund University.

About this article

Cite this article

Zawadzki, A., Liu, Q., Wang, Y. et al. Verapamil Inhibits L-type Calcium Channel Mediated Apoptosis in Human Colon Cancer Cells. Dis Colon Rectum 51, 1696–1702 (2008). https://doi.org/10.1007/s10350-008-9372-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10350-008-9372-7

KEY WORDS

Search

Navigation