Skip to main content

Advertisement

SpringerLink
Log in

Chemical Inhibitors of the Calcium Entry Channel TRPV6

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Calcium entry channels in the plasma membrane are thought to play a major role in maintaining cellular Ca2+ levels, crucial for growth and survival of normal and cancer cells. The calcium-selective channel TRPV6 is expressed in prostate, breast, and other cancer cells. Its expression coincides with cancer progression, suggesting that it drives cancer cell growth. However, no specific inhibitors for TRPV6 have been identified thus far.

Methods

To develop specific TRPV6 inhibitors, we synthesized molecules based on the lead compound TH-1177, reported to inhibit calcium entry channels in prostate cancer cells in vitro and in vivo.

Results

We found that one of our compounds (#03) selectively inhibited TRPV6 over five times better than TRPV5, whereas TH-1177 and the other synthesized compounds preferentially inhibited TRPV5. The IC50 value for growth inhibition by blocking endogenous Ca2+ entry channels in the LNCaP human prostate cancer cell line was 0.44 ± 0.07 μM compared to TH-1177 (50 ± 0.4 μM).

Conclusions

These results suggest that compound #03 is a relatively selective and potent inhibitor for TRPV6 and that it is an interesting lead compound for the treatment of prostate cancer and other cancers of epithelial origin.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CRAC:

Ca2+ release-activated Ca2+

FBS:

fetal bovine serum

LNCaP:

lymph node carcinoma of the prostate

NFAT:

nuclear factor of activated T-cells

NMM:

N-methylmorpholine

Orai1:

calcium release-activated calcium channel protein 1

PyBOP:

Benzotriazol-1-yl-oxytripyrrolidinophosphonium

SCID:

severe combined immunodeficiency

SOC:

store-operated calcium channel

STIM1:

stromal interaction molecule 1

THF:

Tetrahydrofuran

TRP:

transient receptor potential

REFERENCES

  1. Mettlin C, Jones GW, Murphy GP. Trends in prostate cancer care in the United States, 1974–1990: observations from the patient care evaluation studies of the American College of Surgeons Commission on Cancer. CA Cancer J Clin. 1993;43:83–91.

    Article  CAS  PubMed  Google Scholar 

  2. Mundy GR. Mechanisms of bone metastasis. Cancer. 1997;80:1546–56.

    Article  CAS  PubMed  Google Scholar 

  3. Orr FW, Sanchez-Sweatman OH, Kostenuik P, Singh G. Tumor-bone interactions in skeletal metastasis. Clin Orthop Relat Res 19–33 (1995).

  4. Saitoh H, Hida M, Shimbo T, Nakamura K, Yamagata J, Satoh T. Metastatic patterns of prostatic cancer. Correlation between sites and number of organs involved. Cancer. 1984;54:3078–84.

    Article  CAS  PubMed  Google Scholar 

  5. Chanand JM, Giovannucci EL. Dairy products, calcium, and vitamin D and risk of prostate cancer. Epidemiol Rev. 2001;23:87–92.

    Google Scholar 

  6. Clinton SK, Giovannucci E. Diet, nutrition, and prostate cancer. Annu Rev Nutr. 1998;18:413–40.

    Article  CAS  PubMed  Google Scholar 

  7. Tavani A, Gallus S, Franceschi S, La Vecchia C. Calcium, dairy products, and the risk of prostate cancer. Prostate. 2001;48:118–21.

    Article  CAS  PubMed  Google Scholar 

  8. Putney Jr JW. A model for receptor-regulated calcium entry. Cell Calcium. 1986;7:1–12.

    Article  CAS  PubMed  Google Scholar 

  9. Putney Jr JW. Type 3 inositol 1, 4, 5-trisphosphate receptor and capacitative calcium entry. Cell Calcium. 1997;21:257–61.

    Article  CAS  PubMed  Google Scholar 

  10. Putney Jr JW. Capacitative calcium entry in the nervous system. Cell Calcium. 2003;34:339–44.

    Article  CAS  PubMed  Google Scholar 

  11. Hoth M, Penner R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature. 1992;355:353–6.

    Article  CAS  PubMed  Google Scholar 

  12. Lewis RS, Cahalan MD. Mitogen-induced oscillations of cytosolic Ca2+ and transmembrane Ca2+ current in human leukemic T cells. Cell Regul. 1989;1:99–112.

    CAS  PubMed  Google Scholar 

  13. Zweifach A, Lewis RS. Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc Natl Acad Sci U S A. 1993;90:6295–9.

    Article  CAS  PubMed  Google Scholar 

  14. Shuba YM, Prevarskaya N, Lemonnier L, Van Coppenolle F, Kostyuk PG, Mauroy B, et al. Volume-regulated chloride conductance in the LNCaP human prostate cancer cell line. Am J Physiol Cell Physiol. 2000;279:C1144–54.

    CAS  PubMed  Google Scholar 

  15. Zweifach A, Lewis RS. Rapid inactivation of depletion-activated calcium current (ICRAC) due to local calcium feedback. J Gen Physiol. 1995;105:209–26.

    Article  CAS  PubMed  Google Scholar 

  16. Abdullaev IF, Bisaillon JM, Potier M, Gonzalez JC, Motiani RK, Trebak M. Stim1 and Orai1 mediate CRAC currents and store-operated calcium entry important for endothelial cell proliferation. Circ Res. 2008;103:1289–99.

    Article  CAS  PubMed  Google Scholar 

  17. Gwack Y, Feske S, Srikanth S, Hogan PG, Rao A. Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. Cell Calcium. 2007;42:145–56.

    Article  CAS  PubMed  Google Scholar 

  18. Ng SW, di Capite J, Singaravelu K, Parekh AB. Sustained activation of the tyrosine kinase Syk by antigen in mast cells requires local Ca2+ influx through Ca2+ release-activated Ca2+ channels. J Biol Chem. 2008;283:31348–55.

    Article  CAS  PubMed  Google Scholar 

  19. Stiber J, Hawkins A, Zhang ZS, Wang S, Burch J, Graham V, et al. STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle. Nat Cell Biol. 2008;10:688–97.

    Article  CAS  PubMed  Google Scholar 

  20. Perret S, Cantereau A, Audin J, Dufy B, Georgescauld D. Interplay between Ca2+ release and Ca2+ influx underlies localized hyperpolarization-induced [Ca2+]i waves in prostatic cells. Cell Calcium. 1999;25:297–311.

    Article  CAS  PubMed  Google Scholar 

  21. Vanden Abeele F, Lemonnier L, Thebault S, Lepage G, Parys JB, Shuba Y, et al. Two types of store-operated Ca2+ channels with different activation modes and molecular origin in LNCaP human prostate cancer epithelial cells. J Biol Chem. 2004;279:30326–37.

    Article  CAS  PubMed  Google Scholar 

  22. Vanden Abeele F, Roudbaraki M, Shuba Y, Skryma R, Prevarskaya N. Store-operated Ca2+ current in prostate cancer epithelial cells. Role of endogenous Ca2+ transporter type 1. J Biol Chem. 2003;278:15381–9.

    Article  CAS  PubMed  Google Scholar 

  23. Legrand G, Humez S, Slomianny C, Dewailly E, Vanden Abeele F, Mariot P, et al. Ca2+ pools and cell growth. Evidence for sarcoendoplasmic Ca2 + -ATPases 2B involvement in human prostate cancer cell growth control. J Biol Chem. 2001;276:47608–14.

    Article  CAS  PubMed  Google Scholar 

  24. Tombal B, Weeraratna AT, Denmeade SR, Isaacs JT. Thapsigargin induces a calmodulin/calcineurin-dependent apoptotic cascade responsible for the death of prostatic cancer cells. Prostate. 2000;43:303–17.

    Article  CAS  PubMed  Google Scholar 

  25. Wertz IE, Dixit VM. Characterization of calcium release-activated apoptosis of LNCaP prostate cancer cells. J Biol Chem. 2000;275:11470–7.

    Article  CAS  PubMed  Google Scholar 

  26. Skryma R, Mariot P, Bourhis XL, Coppenolle FV, Shuba Y, Vanden Abeele F, et al. Store depletion and store-operated Ca2+ current in human prostate cancer LNCaP cells: involvement in apoptosis. J Physiol. 2000;527(Pt 1):71–83.

    Article  CAS  PubMed  Google Scholar 

  27. Vanden Abeele F, Skryma R, Shuba Y, Van Coppenolle F, Slomianny C, Roudbaraki M, et al. Bcl-2-dependent modulation of Ca(2+) homeostasis and store-operated channels in prostate cancer cells. Cancer Cell. 2002;1:169–79.

    Article  CAS  PubMed  Google Scholar 

  28. Wissenbach U, Niemeyer BA, Fixemer T, Schneidewind A, Trost C, Cavalie A, et al. Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer. J Biol Chem. 2001;276:19461–8.

    Article  CAS  PubMed  Google Scholar 

  29. Fixemer T, Wissenbach U, Flockerzi V, Bonkhoff H. Expression of the Ca2+ -selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression. Oncogene. 2003;22:7858–61.

    Article  CAS  PubMed  Google Scholar 

  30. Zhuang L, Peng JB, Tou L, Takanaga H, Adam RM, Hediger MA, et al. Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab Invest. 2002;82:1755–64.

    CAS  PubMed  Google Scholar 

  31. Bolanz KA, Hediger MA, Landowski CP. The role of TRPV6 in breast carcinogenesis. Mol Cancer Ther. 2008;7:271–9.

    Article  CAS  PubMed  Google Scholar 

  32. Bodding M, Flockerzi V. Ca2+ dependence of the Ca2+-selective TRPV6 channel. J Biol Chem. 2004;279:36546–52.

    Article  PubMed  Google Scholar 

  33. Schindl R, Kahr H, Graz I, Groschner K, Romanin C. Store depletion-activated CaT1 currents in rat basophilic leukemia mast cells are inhibited by 2-aminoethoxydiphenyl borate. Evidence for a regulatory component that controls activation of both CaT1 and CRAC (Ca(2+) release-activated Ca(2+) channel) channels. J Biol Chem. 2002;277:26950–8.

    Article  CAS  PubMed  Google Scholar 

  34. Lehen’kyi V, Flourakis M, Skryma R, Prevarskaya N. TRPV6 channel controls prostate cancer cell proliferation via Ca(2+)/NFAT-dependent pathways. Oncogene. 2007;26:7380–5.

    Article  PubMed  Google Scholar 

  35. Haverstick DM, Heady TN, Macdonald TL, Gray LS. Inhibition of human prostate cancer proliferation in vitro and in a mouse model by a compound synthesized to block Ca2+ entry. Cancer Res. 2000;60:1002–8.

    CAS  PubMed  Google Scholar 

  36. Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H, Brown EM, et al. Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J Biol Chem. 1999;274:22739–46.

    Article  CAS  PubMed  Google Scholar 

  37. Peng JB, Zhuang L, Berger UV, Adam RM, Williams BJ, Brown EM, et al. CaT1 expression correlates with tumor grade in prostate cancer. Biochem Biophys Res Commun. 2001;282:729–34.

    Article  CAS  PubMed  Google Scholar 

  38. Imai YN, Ryu S, Oiki S. Docking model of drug binding to the human ether-a-go-go potassium channel guided by tandem dimer mutant patch-clamp data: a synergic approach. J Med Chem. 2009;52:1630–8.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

This study was supported by the Swiss National Science Foundation (Hediger), Novartis Foundation (Hediger), NIH/NCI (Hediger), Marie Curie Reintegration Grant (Hediger) and Bernese Cancer League (Landowski). We thank Leah Witton for her helpful comments on the manuscript.

Author information

Author notes

  1. Christopher P. Landowski

    Present address: VTT Technical Research Center of Finland, Espoo, Finland

  2. Katrin A. Bolanz

    Present address: Agroscope, Swiss Federal Office for Agriculture, Bern, Switzerland

  3. Yoshiro Suzuki

    Present address: National Institute for Physiological Sciences, Okazaki, Japan

Authors and Affiliations

  1. Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, CH-3012, Switzerland

    Christopher P. Landowski, Katrin A. Bolanz, Yoshiro Suzuki & Matthias A. Hediger

  2. Swiss National Center of Competence in Research, NCCR-TransCure, University of Berne, Bern, Switzerland

    Matthias A. Hediger

Authors
  1. Christopher P. Landowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katrin A. Bolanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshiro Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthias A. Hediger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias A. Hediger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Landowski, C.P., Bolanz, K.A., Suzuki, Y. et al. Chemical Inhibitors of the Calcium Entry Channel TRPV6. Pharm Res 28, 322–330 (2011). https://doi.org/10.1007/s11095-010-0249-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0249-9

KEY WORDS

Search

Navigation