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

Abstract

To investigate the therapeutic effect of methylselenocysteine (MSC) combined with tamoxifen in MCF-7 breast cancer xenograft and the underlying mechanisms. MCF-7 breast cancer xenograft was established in ovariectomized female athymic nude mice and treated with tamoxifen and/or MSC. Tumor size was measured twice a week. Immunohistochemistry and TUNEL assays were used to measure ERalpha expression, ERalpha target genes (progesterone receptor (PR) and cyclin D1 expression), Ki-67 index, apoptosis and microvessel density. Combined treatment with tamoxifen and MSC synergistically inhibited tumor growth compared to MSC alone and tamoxifen alone. MSC alone or MSC + tamoxifen significantly reduced ERalpha, PR and cyclin D1, Ki67 index and microvessel density while increasing apoptosis in tumor tissues. These findings demonstrate synergistic growth inhibition of ERalpha positive breast cancer xenografts by combination of tamoxifen with organic selenium compounds. Organic selenium may provide added benefit when combined with tamoxifen in adjuvant therapy or prevention.

KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor α positive breast cancer

“…The procedure was followed as described earlier in our laboratory [19]. Briefly, mice were anesthetized using ketamine.…”

“…Mice with palpable tumors were divided into four groups of five animals each. All mice were implanted subcutaneously estrogen pellets [0.72 mg of 17b-estradiol 60-day release] (Innovative Research of America, Sarasota, FL) above the shoulders using a 10-gauge trochar [19].…”

“…To determine the percentage of proliferating cells, paraffinembedded sections were stained for Ki67, as previously described in our laboratory [19]. For quantification, three randomly selected bright field microscope images (magnification 2009) per sample were obtained as described above.…”

“…TAM treatment (44.1%) were observed when compared with E2 control. Progesterone receptor (PR) and cyclin D1 are ERa regulated genes and surrogate markers of functional ERa signaling [19]. PR protein expression was not affected by either TAM (45.15%) or KX-01 (44.56%) (P = 0.832 and 0.185, respectively) but combination treatment resulted in a significant reduction of PR (32.71%, P \ 0.01) compared to E2 control (50.41%) or either drug alone (Fig.…”

Nutritional and supranutritional levels of selenate differentially suppress prostate tumor growth in adult but not young nude mice

“…Based on these observations, it is conceivable that selenium at the supranutritional levels may inhibit prostate tumorigenesis through the suppression of angiogenesis. In agreement with this hypothesis, selenium compounds, in combination with other chemopreventive agents, have been shown to suppress angiogenesis in mouse models of cancer [36][37][38]. Since blood vessels are present mainly in the outer surface of a tumor, increased angiogenesis would deplete nutrient supplies to cells inside the tumors, resulting in increased cell death in the softer Se− tumors.…”