Direct, differential effects of tamoxifen, 4-hydroxytamoxifen, and raloxifene on cardiac myocyte contractility and calcium handling

Tamoxifen (Tam), a selective estrogen receptor modulator, is in wide clinical use for the treatment and prevention of breast cancer. High Tam doses have been used for treatment of gliomas and cancers with multiple drug resistance, but long QT Syndrome is a side effect. Tam is also used experimentall...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2013-10, Vol.8 (10), p.e78768-e78768
Main Authors: Asp, Michelle L, Martindale, Joshua J, Metzger, Joseph M
Format: Article
Language:English
Subjects:
Acute effects
Animal tissues
Animals
Biology
Biomechanical Phenomena - drug effects
Breast cancer
Calcium
Calcium - metabolism
Cancer
Cardiomyopathy
Contraction
Drug dosages
Drug resistance
Drugs
Estrogen
Estrogen receptors
Estrogens
Female
Genes
Handling
Heart
Heart diseases
Laboratory animals
Long QT syndrome
Mechanical properties
Metabolism
Metabolites
Mice
Multidrug resistance
Muscle contraction
Muscle Contraction - drug effects
Myocytes
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - physiology
Patients
Physiology
Raloxifene
Raloxifene Hydrochloride - pharmacology
Rats
Rats, Sprague-Dawley
Rodents
Sarcomeres - drug effects
Sarcomeres - metabolism
Sarcomeres - physiology
Side effects
Studies
Tamoxifen
Tamoxifen - analogs & derivatives
Tamoxifen - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Tamoxifen (Tam), a selective estrogen receptor modulator, is in wide clinical use for the treatment and prevention of breast cancer. High Tam doses have been used for treatment of gliomas and cancers with multiple drug resistance, but long QT Syndrome is a side effect. Tam is also used experimentally in mice for inducible gene knockout in numerous tissues, including heart; however, the potential direct effects of Tam on cardiac myocyte mechanical function are not known. The goal of this study was to determine the direct, acute effects of Tam, its active metabolite 4-hydroxytamoxifen (4OHT), and related drug raloxifene (Ral) on isolated rat cardiac myocyte mechanical function and calcium handling. Tam decreased contraction amplitude, slowed relaxation, and decreased Ca²⁺ transient amplitude. Effects were primarily observed at 5 and 10 μM Tam, which is relevant for high dose Tam treatment in cancer patients as well as Tam-mediated gene excision in mice. Myocytes treated with 4OHT responded similarly to Tam-treated cells with regard to both contractility and calcium handling, suggesting an estrogen-receptor independent mechanism is responsible for the effects. In contrast, Ral increased contraction and Ca²⁺ transient amplitudes. At 10 μM, all drugs had a time-dependent effect to abolish cellular contraction. In conclusion, Tam, 4OHT, and Ral adversely and differentially alter cardiac myocyte contractility and Ca²⁺ handling. These findings have important implications for understanding the Tam-induced cardiomyopathy in gene excision studies and may be important for understanding effects on cardiac performance in patients undergoing high-dose Tam therapy.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0078768