Abstract
BackgroundTamoxifen is the standard endocrine therapy for ER+ breast cancer; however, many women still relapse after long-term therapy. 3-Bromopyruvate, a glycolytic inhibitor, has shown high selective anti-tumor activity in vitro, and in vivo. The aim of this study was to evaluate the possible augmentation of the effect of tamoxifen via reprograming cancer cell metabolism using 3-bromopyruvate.MethodsAn in vitro screening of antitumor activity as well as the apoptotic, anti-metastatic, and anti-angiogenic potentials of the combination therapy were carried out using different techniques on breast cancer cell lines MCF7and T47D. In addition the antitumor effect of the combined therapy was done on mice bearing tumor.ResultsOur results showed modulation in apoptosis, angiogenesis and metastatic potential by either drug alone; however, their combination has surpassed that of the individual one. Combination regimen enhanced activated caspases-3, 7 and 9, as well as oxidative stress, signified by increased malondialdehyde and decreased glutathione level. Additionally, the angiogenesis and metastasis markers, including hypoxia inducing factor-1α, vascular endothelia growth factor, and metaloproteinases-2 and 9 were decreased after using the combination regimen. These results were further confirmed by the in vivo study, which depicted a decrease in the tumor volume and angiogenesis and an increase in oxidative stress as well.Conclusion3-bromopyruvate could be a valuable compound when added with tamoxifen in breast cancer treatment.
Highlights
Tamoxifen is the standard endocrine therapy for ER+ breast cancer; many women still relapse after long-term therapy. 3-Bromopyruvate, a glycolytic inhibitor, has shown high selective anti-tumor activity in vitro, and in vivo
Chemicals RPMI-1640 Medium, fetal bovine serum, dimethylsulfoxide (DMSO), Ellman’s reagent [5,5-Dithio-bis-(2-nitro benzoic acid)], β-mercaptoethanol, reduced glutathione, sodium dodecyl sulfate (SDS), sodium bicarbonate, 1,1.3,3-tetramethoxypropane, trichloroacetic acid (TCA) and thiobarbituric acid were all purchased from Sigma Aldrich Chemical Co
In vitro 3-BP enhances cytotoxicity of TAM on MCF7 and T47D cells Figure 1 showed that treatment of MCF7 [A] and T47D [B] cells with various concentrations (10–50 μM) of TAM or 3-BP for 48 h caused a concentration dependent decrease in cell survival
Summary
Tamoxifen is the standard endocrine therapy for ER+ breast cancer; many women still relapse after long-term therapy. 3-Bromopyruvate, a glycolytic inhibitor, has shown high selective anti-tumor activity in vitro, and in vivo. Tamoxifen is the standard endocrine therapy for ER+ breast cancer; many women still relapse after long-term therapy. The aim of this study was to evaluate the possible augmentation of the effect of tamoxifen via reprograming cancer cell metabolism using 3-bromopyruvate. Breast cancer was estimated one of the most commonly diagnosed cancers worldwide among women (11.9 %). The development of a combination therapy that increases the efficacy of TAM has been investigated in several studies, using vitamin E [8] and green tea [9]. Mounting evidence supports, that reprogramming of cellular metabolism in cancer cells is linked to failure of treatment, and drug resistance in cancer therapy [10]
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