Methylseleninic acid synergizes with tamoxifen to induce caspase-mediated apoptosis in breast cancer cells.

Abstract

Tamoxifen has efficacy as a breast cancer therapy and chemoprevention agent. However, toxicity and resistance to tamoxifen limit its clinical application. There is an urgent need to develop compounds that may be combined with tamoxifen to improve efficacy and overcome toxicity and resistance. We showed previously that the organoselenium compound methylseleninic acid (MSA) increased the growth-inhibitory effect of tamoxifen and reversed tamoxifen resistance in breast cancer cells. In this study, we examined the mechanism for induction of apoptosis by MSA combined with tamoxifen in tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. 4-hydroxytamoxifen (TAM; 10(-7) mol/L) alone resulted in cell cycle arrest but no apoptosis, whereas MSA alone (10 micromol/L) induced apoptosis in tamoxifen-sensitive cells. Combination of MSA with TAM resulted in a synergistic apoptosis in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells compared with either agent alone. MSA and MSA combined with TAM induced apoptosis through the intrinsic, mitochondrial apoptotic pathway. MSA induced a sequential activation of caspase-9 and then caspase-8. These results indicate that the growth inhibition synergy and reversal of tamoxifen resistance by combination of selenium with tamoxifen occurs via a tamoxifen-induced cell cycle arrest, allowing more cells to enter the intrinsic apoptotic pathway elicited by selenium.

• Authors: Zengshan Li, Latonya Carrier, Brian G Rowan
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 9 Pg. 3056-63 (Sep 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18790785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Caspase Inhibitors
• Membrane Proteins
• Organoselenium Compounds
• Proto-Oncogene Proteins
• Tamoxifen
• Cytochromes c
• methylselenic acid
• Poly(ADP-ribose) Polymerases
• Caspase 8
• Caspase 9

Topics

• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Bcl-2-Like Protein 11
• Blotting, Western
• Breast Neoplasms (enzymology, pathology)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Caspase Inhibitors
• Cell Line, Tumor
• Cytochromes c (metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Enzyme Activation (drug effects)
• Female
• G1 Phase (drug effects)
• Humans
• Membrane Proteins (metabolism)
• Mitochondria (enzymology)
• Models, Biological
• Organoselenium Compounds (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Tamoxifen (pharmacology)