Tamoxifen and the farnesyl transferase inhibitor FTI-277 synergize to inhibit growth in estrogen receptor-positive breast tumor cell lines

Farnesyl transferase inhibitors (FTIs) serve to specifically inhibit farnesyl isoprenoid lipid modification of proteins. Although originally developed as anti-Ras oncoprotein drugs, it now appears that these compounds function independently of Ras. FTIs have been shown to inhibit transformation by a...

Full description

Saved in:
Bibliographic Details
Published in:Breast cancer research and treatment 2003-03, Vol.78 (1), p.59-67
Main Authors: ELLIS, Chad A, VOS, Michele D, WICKLINE, Meredith, RILEY, Christine, VALLECORSA, Teresa, TELFORD, William G, ZUJEWSKI, Joanne, CLARK, Geoffrey J
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - physiopathology
Cancer research
Cancer therapies
Chemotherapy
Drug Synergism
Enzyme Inhibitors - therapeutic use
Female
Humans
Medical sciences
Methionine - analogs & derivatives
Methionine - therapeutic use
Pharmacology. Drug treatments
Receptors, Estrogen - metabolism
Tamoxifen - therapeutic use
Tumor Cells, Cultured
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:Farnesyl transferase inhibitors (FTIs) serve to specifically inhibit farnesyl isoprenoid lipid modification of proteins. Although originally developed as anti-Ras oncoprotein drugs, it now appears that these compounds function independently of Ras. FTIs have been shown to inhibit transformation by a variety of mechanisms, including apoptosis involving cytochrome c release from mitochondria. Tamoxifen exhibits both anti-estrogenic and estrogenic properties and is widely used as an estrogen antagonist for the treatment of estrogen receptor (ER) positive human breast tumors. Tamoxifen can induce ER-dependent apoptosis in human breast tumor cells by a mechanism involving the Bcl2/mitochondrial arm of the apoptotic machinery. Since tamoxifen and FTIs may stimulate distinct components of the mitochondrial-based apoptotic machinery, we reasoned that their effects might be synergistic. Here we show that anti-estrogens and an FTI (FTI-277) synergize to inhibit cell growth and enhance cell death in ER positive, human breast tumor cell lines. However, the drugs exhibited only additive effects on an ER negative cell line. Analysis of treated ER positive T-47D cells demonstrated that a synergistic increase in apoptosis was induced, as measured by increased caspase 3 activity. Thus, tamoxifen and FTIs may synergize to promote apoptotic cell death in ER positive human breast tumor cells.
ISSN:0167-6806
1573-7217
DOI:10.1023/A:1022105511409