Chemical inhibitors of the calcium entry channel TRPV6

Christopher Landowski, K.A. Bolanz, Y. Suzuki, M.A. Hediger (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

22 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)322-330
Number of pages9
JournalPharmaceutical Research
Volume28
Issue number2
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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Calcium Channels
Cells
Calcium
Lead compounds
Prostatic Neoplasms
Neoplasms
Growth
Cell growth
Cell membranes
Inhibitory Concentration 50
Prostate
Cell Membrane
Breast Neoplasms
Cell Line
Molecules
Survival
TRPV6 channel
TH 1177
Lead

Keywords

  • breast cancer
  • calcium channel
  • chemical inhibitors
  • prostate cancer
  • TRPV6

Cite this

Landowski, Christopher ; Bolanz, K.A. ; Suzuki, Y. ; Hediger, M.A. / Chemical inhibitors of the calcium entry channel TRPV6. In: Pharmaceutical Research. 2011 ; Vol. 28, No. 2. pp. 322-330.
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Chemical inhibitors of the calcium entry channel TRPV6. / Landowski, Christopher; Bolanz, K.A.; Suzuki, Y.; Hediger, M.A. (Corresponding Author).

In: Pharmaceutical Research, Vol. 28, No. 2, 2011, p. 322-330.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Chemical inhibitors of the calcium entry channel TRPV6

AU - Landowski, Christopher

AU - Bolanz, K.A.

AU - Suzuki, Y.

AU - Hediger, M.A.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

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KW - calcium channel

KW - chemical inhibitors

KW - prostate cancer

KW - TRPV6

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DO - 10.1007/s11095-010-0249-9

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