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The effects of tamoxifen and toremifene on bone cells involve changes in plasma membrane ion conductance

Lehenkari, Petri; Parikka, Vilhelmiina; Rautiala, Timo J; Weckström, Matti; Dahllund, Johanna; Härkönen, Pirkko LU and Väänänen, H Kalervo (2003) In Journal of Bone and Mineral Research 18(3). p.473-481
Abstract
Selective estrogen receptor modulators (SERMs), tamoxifen (Tam) and toremifene (Tor), are widely used in the treatment of breast cancer. In addition, they have been demonstrated to prevent estrogen deficiency-induced bone loss in postmenopausal women. These effects are thought to be caused by the interaction of the SERMs with the estrogen receptor, although SERMs have also been shown to conduct non-receptor-mediated effects such as rapid changes in membrane functions. We compared the effects of Tam, Tor, and 17β-estradiol (E2) on the viability of rat osteoclasts and osteoblasts. Both Tam and Tor were found to cause osteoclast apoptosis in in vitro cultures, which was reversed by E2. In addition, at higher concentration (10 μM), both SERMs... (More)
Selective estrogen receptor modulators (SERMs), tamoxifen (Tam) and toremifene (Tor), are widely used in the treatment of breast cancer. In addition, they have been demonstrated to prevent estrogen deficiency-induced bone loss in postmenopausal women. These effects are thought to be caused by the interaction of the SERMs with the estrogen receptor, although SERMs have also been shown to conduct non-receptor-mediated effects such as rapid changes in membrane functions. We compared the effects of Tam, Tor, and 17β-estradiol (E2) on the viability of rat osteoclasts and osteoblasts. Both Tam and Tor were found to cause osteoclast apoptosis in in vitro cultures, which was reversed by E2. In addition, at higher concentration (10 μM), both SERMs had an estrogen receptor-independent effect, which involved interaction with the plasma membrane as demonstrated with UMR-108 osteosarcoma cells by Tam and Tor, but not E2. A leak of protons leading to changes in intracellular pH was shown both in medullary bone derived membrane vesicles and in intact cells. These effects were followed by a rapid loss of cell viability and subsequent cell lysis. Our results show that both Tam and Tor have an ionophoric effect on the plasma membranes of bone cells and that these SERMs differed in this ability: Tor induced rapid membrane depolarization only in the presence of high concentration of potassium. These non-receptor-mediated effects may be involved in therapeutic responses and explain some clinical side effects associated with the treatment of patients with these SERMs (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Bone and Mineral Research
volume
18
issue
3
pages
473 - 481
publisher
AMBMR
external identifiers
  • scopus:0037370621
ISSN
1523-4681
DOI
10.1359/jbmr.2003.18.3.473
language
English
LU publication?
yes
id
7e17677f-dcc5-45a0-9bb8-c128a2afe2a7 (old id 1127608)
date added to LUP
2008-06-05 14:24:33
date last changed
2018-10-03 09:29:13
@article{7e17677f-dcc5-45a0-9bb8-c128a2afe2a7,
  abstract     = {Selective estrogen receptor modulators (SERMs), tamoxifen (Tam) and toremifene (Tor), are widely used in the treatment of breast cancer. In addition, they have been demonstrated to prevent estrogen deficiency-induced bone loss in postmenopausal women. These effects are thought to be caused by the interaction of the SERMs with the estrogen receptor, although SERMs have also been shown to conduct non-receptor-mediated effects such as rapid changes in membrane functions. We compared the effects of Tam, Tor, and 17β-estradiol (E2) on the viability of rat osteoclasts and osteoblasts. Both Tam and Tor were found to cause osteoclast apoptosis in in vitro cultures, which was reversed by E2. In addition, at higher concentration (10 μM), both SERMs had an estrogen receptor-independent effect, which involved interaction with the plasma membrane as demonstrated with UMR-108 osteosarcoma cells by Tam and Tor, but not E2. A leak of protons leading to changes in intracellular pH was shown both in medullary bone derived membrane vesicles and in intact cells. These effects were followed by a rapid loss of cell viability and subsequent cell lysis. Our results show that both Tam and Tor have an ionophoric effect on the plasma membranes of bone cells and that these SERMs differed in this ability: Tor induced rapid membrane depolarization only in the presence of high concentration of potassium. These non-receptor-mediated effects may be involved in therapeutic responses and explain some clinical side effects associated with the treatment of patients with these SERMs},
  author       = {Lehenkari, Petri and Parikka, Vilhelmiina and Rautiala, Timo J and Weckström, Matti and Dahllund, Johanna and Härkönen, Pirkko and Väänänen, H Kalervo},
  issn         = {1523-4681},
  language     = {eng},
  number       = {3},
  pages        = {473--481},
  publisher    = {AMBMR},
  series       = {Journal of Bone and Mineral Research},
  title        = {The effects of tamoxifen and toremifene on bone cells involve changes in plasma membrane ion conductance},
  url          = {http://dx.doi.org/10.1359/jbmr.2003.18.3.473},
  volume       = {18},
  year         = {2003},
}