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Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells

Tamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological conce... Full description

Journal Title: Apoptosis (London) 2005-12, Vol.10 (6), p.1395-1410
Main Author: Kallio, A
Other Authors: Zheng, A , Dahllund, J , Heiskanen, K M , Härkönen, P
Format: Electronic Article Electronic Article
Language: English
Subjects:
ROS
Publisher: Netherlands: Springer
ID: ISSN: 1360-8185
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recordid: cdi_swepub_primary_oai_lup_lub_lu_se_818c5250_10f4_4e76_aee7_ccec757a1307
title: Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells
format: Article
creator:
  • Kallio, A
  • Zheng, A
  • Dahllund, J
  • Heiskanen, K M
  • Härkönen, P
subjects:
  • Antineoplastic Agents, Hormonal - pharmacology
  • Apoptosis
  • Apoptosis - drug effects
  • Bongkrekic Acid - pharmacology
  • Breast cancer
  • Breast Neoplasms - enzymology
  • Breast Neoplasms - pathology
  • Cancer cells
  • Caspase 9 - metabolism
  • cell death
  • Cell Line, Tumor
  • Clinical Medicine
  • Cytochromes c - secretion
  • Drug Screening Assays, Antitumor
  • Enzyme Activation - drug effects
  • Estradiol - analogs & derivatives
  • Estradiol - pharmacology
  • Estrogens - deficiency
  • Female
  • Humans
  • Klinisk medicin
  • MCF-7
  • Medical and Health Sciences
  • Medicin och hälsovetenskap
  • Membrane Potential, Mitochondrial - drug effects
  • mitochondria
  • Mitochondria - drug effects
  • Mitochondria - enzymology
  • Mitochondria - metabolism
  • Mitochondria - secretion
  • Onium Compounds - pharmacology
  • Poly(ADP-ribose) Polymerases - metabolism
  • Proteins
  • rapid
  • Reactive Oxygen Species - metabolism
  • ROS
  • Tamoxifen - pharmacology
  • Toremifene - pharmacology
ispartof: Apoptosis (London), 2005-12, Vol.10 (6), p.1395-1410
description: Tamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological concentrations) has also rapid nongenomic effects. Here we studied the mechanisms by which Tam exerts rapid effects on breast cancer cell viability. In serum-free medium 5-7 microM Tam induced death of MCF-7 and MDA-MB-231 cells in a time-dependent manner in less than 60 min. This was associated with release of mitochondrial cytochrome c, a decrease of mitochondrial membrane potential and an increase in production of reactive oxygen species (ROS). This suggests that disruption of mitochondrial function has a primary role in the acute death response of the cells. Accordingly, bongkrekic acid, an inhibitor of mitochondrial permeability transition, was able to protect MCF-7 cells against Tam. Rapid cell death induction by Tam was not associated with immediate activation of caspase-9 or cleavage of poly (ADP-ribose) polymerase. It was not blocked by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone either. Diphenylene ionodium (DPI), an inhibitor of NADPH oxidase, was able to prevent Tam-induced cell death but not cytochrome c release, which suggests that ROS act distal to cytochrome c. The pure antiestrogen ICI 182780 (1 microM) could partly oppose the effect of Tam in estrogen receptor positive MCF-7 cells, but not in estrogen receptor negative MDA-MB-231 cells. Pre-culturing MCF-7 cells in the absence of 17beta-estradiol (E(2)) or in the presence of a low Tam concentration (1 microM) made the cells even more susceptible to rapid death induction by 5 or 7 microM Tam. This effect was associated with decreased levels of the anti-apoptotic proteins Bcl-X(L) and Bcl-2. In conclusion, our results demonstrate induction of a rapid mitochondrial cell death program in breast cancer cells at pharmacological concentrations of Tam, which are achievable in tumor tissue of Tam-treated breast cancer patients. These mechanisms may contribute to the ability of Tam therapy to induce death of breast cancer cells.
language: eng
source:
identifier: ISSN: 1360-8185
fulltext: no_fulltext
issn:
  • 1360-8185
  • 1573-675X
url: Link


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titleRole of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells
creatorKallio, A ; Zheng, A ; Dahllund, J ; Heiskanen, K M ; Härkönen, P
creatorcontribKallio, A ; Zheng, A ; Dahllund, J ; Heiskanen, K M ; Härkönen, P
descriptionTamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological concentrations) has also rapid nongenomic effects. Here we studied the mechanisms by which Tam exerts rapid effects on breast cancer cell viability. In serum-free medium 5-7 microM Tam induced death of MCF-7 and MDA-MB-231 cells in a time-dependent manner in less than 60 min. This was associated with release of mitochondrial cytochrome c, a decrease of mitochondrial membrane potential and an increase in production of reactive oxygen species (ROS). This suggests that disruption of mitochondrial function has a primary role in the acute death response of the cells. Accordingly, bongkrekic acid, an inhibitor of mitochondrial permeability transition, was able to protect MCF-7 cells against Tam. Rapid cell death induction by Tam was not associated with immediate activation of caspase-9 or cleavage of poly (ADP-ribose) polymerase. It was not blocked by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone either. Diphenylene ionodium (DPI), an inhibitor of NADPH oxidase, was able to prevent Tam-induced cell death but not cytochrome c release, which suggests that ROS act distal to cytochrome c. The pure antiestrogen ICI 182780 (1 microM) could partly oppose the effect of Tam in estrogen receptor positive MCF-7 cells, but not in estrogen receptor negative MDA-MB-231 cells. Pre-culturing MCF-7 cells in the absence of 17beta-estradiol (E(2)) or in the presence of a low Tam concentration (1 microM) made the cells even more susceptible to rapid death induction by 5 or 7 microM Tam. This effect was associated with decreased levels of the anti-apoptotic proteins Bcl-X(L) and Bcl-2. In conclusion, our results demonstrate induction of a rapid mitochondrial cell death program in breast cancer cells at pharmacological concentrations of Tam, which are achievable in tumor tissue of Tam-treated breast cancer patients. These mechanisms may contribute to the ability of Tam therapy to induce death of breast cancer cells.
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2DOI: 10.1007/s10495-005-2137-z
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languageeng
publisherNetherlands: Springer
subjectAntineoplastic Agents, Hormonal - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Bongkrekic Acid - pharmacology ; Breast cancer ; Breast Neoplasms - enzymology ; Breast Neoplasms - pathology ; Cancer cells ; Caspase 9 - metabolism ; cell death ; Cell Line, Tumor ; Clinical Medicine ; Cytochromes c - secretion ; Drug Screening Assays, Antitumor ; Enzyme Activation - drug effects ; Estradiol - analogs & derivatives ; Estradiol - pharmacology ; Estrogens - deficiency ; Female ; Humans ; Klinisk medicin ; MCF-7 ; Medical and Health Sciences ; Medicin och hälsovetenskap ; Membrane Potential, Mitochondrial - drug effects ; mitochondria ; Mitochondria - drug effects ; Mitochondria - enzymology ; Mitochondria - metabolism ; Mitochondria - secretion ; Onium Compounds - pharmacology ; Poly(ADP-ribose) Polymerases - metabolism ; Proteins ; rapid ; Reactive Oxygen Species - metabolism ; ROS ; Tamoxifen - pharmacology ; Toremifene - pharmacology
ispartofApoptosis (London), 2005-12, Vol.10 (6), p.1395-1410
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1Zheng, A
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descriptionTamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological concentrations) has also rapid nongenomic effects. Here we studied the mechanisms by which Tam exerts rapid effects on breast cancer cell viability. In serum-free medium 5-7 microM Tam induced death of MCF-7 and MDA-MB-231 cells in a time-dependent manner in less than 60 min. This was associated with release of mitochondrial cytochrome c, a decrease of mitochondrial membrane potential and an increase in production of reactive oxygen species (ROS). This suggests that disruption of mitochondrial function has a primary role in the acute death response of the cells. Accordingly, bongkrekic acid, an inhibitor of mitochondrial permeability transition, was able to protect MCF-7 cells against Tam. Rapid cell death induction by Tam was not associated with immediate activation of caspase-9 or cleavage of poly (ADP-ribose) polymerase. It was not blocked by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone either. Diphenylene ionodium (DPI), an inhibitor of NADPH oxidase, was able to prevent Tam-induced cell death but not cytochrome c release, which suggests that ROS act distal to cytochrome c. The pure antiestrogen ICI 182780 (1 microM) could partly oppose the effect of Tam in estrogen receptor positive MCF-7 cells, but not in estrogen receptor negative MDA-MB-231 cells. Pre-culturing MCF-7 cells in the absence of 17beta-estradiol (E(2)) or in the presence of a low Tam concentration (1 microM) made the cells even more susceptible to rapid death induction by 5 or 7 microM Tam. This effect was associated with decreased levels of the anti-apoptotic proteins Bcl-X(L) and Bcl-2. In conclusion, our results demonstrate induction of a rapid mitochondrial cell death program in breast cancer cells at pharmacological concentrations of Tam, which are achievable in tumor tissue of Tam-treated breast cancer patients. These mechanisms may contribute to the ability of Tam therapy to induce death of breast cancer cells.
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1Apoptosis
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3Bongkrekic Acid - pharmacology
4Breast cancer
5Breast Neoplasms - enzymology
6Breast Neoplasms - pathology
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8Caspase 9 - metabolism
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12Cytochromes c - secretion
13Drug Screening Assays, Antitumor
14Enzyme Activation - drug effects
15Estradiol - analogs & derivatives
16Estradiol - pharmacology
17Estrogens - deficiency
18Female
19Humans
20Klinisk medicin
21MCF-7
22Medical and Health Sciences
23Medicin och hälsovetenskap
24Membrane Potential, Mitochondrial - drug effects
25mitochondria
26Mitochondria - drug effects
27Mitochondria - enzymology
28Mitochondria - metabolism
29Mitochondria - secretion
30Onium Compounds - pharmacology
31Poly(ADP-ribose) Polymerases - metabolism
32Proteins
33rapid
34Reactive Oxygen Species - metabolism
35ROS
36Tamoxifen - pharmacology
37Toremifene - pharmacology
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titleRole of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells
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31Poly(ADP-ribose) Polymerases - metabolism
32Proteins
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34Reactive Oxygen Species - metabolism
35ROS
36Tamoxifen - pharmacology
37Toremifene - pharmacology
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abstractTamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological concentrations) has also rapid nongenomic effects. Here we studied the mechanisms by which Tam exerts rapid effects on breast cancer cell viability. In serum-free medium 5-7 microM Tam induced death of MCF-7 and MDA-MB-231 cells in a time-dependent manner in less than 60 min. This was associated with release of mitochondrial cytochrome c, a decrease of mitochondrial membrane potential and an increase in production of reactive oxygen species (ROS). This suggests that disruption of mitochondrial function has a primary role in the acute death response of the cells. Accordingly, bongkrekic acid, an inhibitor of mitochondrial permeability transition, was able to protect MCF-7 cells against Tam. Rapid cell death induction by Tam was not associated with immediate activation of caspase-9 or cleavage of poly (ADP-ribose) polymerase. It was not blocked by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone either. Diphenylene ionodium (DPI), an inhibitor of NADPH oxidase, was able to prevent Tam-induced cell death but not cytochrome c release, which suggests that ROS act distal to cytochrome c. The pure antiestrogen ICI 182780 (1 microM) could partly oppose the effect of Tam in estrogen receptor positive MCF-7 cells, but not in estrogen receptor negative MDA-MB-231 cells. Pre-culturing MCF-7 cells in the absence of 17beta-estradiol (E(2)) or in the presence of a low Tam concentration (1 microM) made the cells even more susceptible to rapid death induction by 5 or 7 microM Tam. This effect was associated with decreased levels of the anti-apoptotic proteins Bcl-X(L) and Bcl-2. In conclusion, our results demonstrate induction of a rapid mitochondrial cell death program in breast cancer cells at pharmacological concentrations of Tam, which are achievable in tumor tissue of Tam-treated breast cancer patients. These mechanisms may contribute to the ability of Tam therapy to induce death of breast cancer cells.
copNetherlands
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pmid16215679
doi10.1007/s10495-005-2137-z