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 À7 mol/L) alone resulted in cell cycle arrest but no apoptosis, whereas MSA alone (10 Mmol/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.

Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis

“…Our previous in vitro studies demonstrated synergy between tamoxifen and organic selenium compounds for growth inhibition and apoptosis induction in breast cancer cell lines [20]. The present study extends the finding of synergy between selenium and tamoxifen in vitro, to demonstrate similar synergy in vivo through measurement of breast tumor xenograft growth, apoptosis, angiogenesis and ER signaling.…”

Effects of Selenite and Genistein on G2/M Cell Cycle Arrest and Apoptosis in Human Prostate Cancer Cells

“…In addition to combinations of selenium with other chemopreventive agents, recent studies have shown that selenium compounds also enhanced the effects of radiation and chemotherapeutic agents on cancer cells. Results from ours and others suggest that Se may have the potential to enhance the efficacy of other chemopreventive or chemotherapeutic agents (42–46). …”

Combination Treatment of Tamoxifen with Risperidone in Breast Cancer

“…Based on accumulating evidence suggesting activation of caspase-dependent apoptosis by tamoxifen [5], [22], [23], we examined the effects on caspases cleavage and expression by treatment of tamoxifen with or without risperidone. As shown in Figure 5, tamoxifen treatment induced pronounced cleavage of caspase 9, caspase 7, and caspase 3 (5.83±0.35-fold, 3.52±0.03-fold, and 1.95±0.13-fold to control, respectively).…”

“…Moreover, cytostasis, induced by cell cycle arrest, is a condition that is poorly tolerated by any cell and must either be escaped or resolved by cellular death, hence the apoptotic activity of these primarily cytostatic agents [21]. It has been reported that tamoxifen-induced apoptosis involves cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP-ribose polymerase (PARP) [5], [22], [23]. Anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax are also important effectors in the regulation of tamoxifen-induced cell death [5], [24].…”