Dialyl-sulfide with chalcone prevent breast cancer prohibiting SULT1E1 malregulations and oxidant-stress induced HIF1a-MMPs induction

Abstract

Abstract Background: In some breast cancers, decreased estrogen-sulfotransferase (SULT1E1) and its inactivation caused by oxidative-stress lead to elevated E2 levels as well as hypoxia-inducible tissue-damaging factors. Methods: Here, matrix-metalloproteases (MMP2/9) activity and SULT1E1-HIF1α protein/gene expression (Western-blot/RTPCR) were assessed in human breast-cancers versus their adjacent-tissues. Oxidant-stress neutralizer, chalcone (α,β unsaturated ketone) and SULT1E1-inducer pure vdialyl-sulfide (source garlic; Allium sativum) were tested to prevent cancer causing factors in rat, in-vitro and in-vivo model. The antioxidant-enzymres SOD1, catalase, GPx and LDH, and matrix-degenerating MMP2/9 activities were assessed (gel-zymogram). Histoarchitecture (HE-staining) and tissue SULT1E1-localization (immuno-histochemistry) were screened. Extensive statistical-analysis were performed. Results: Human cancer-tissue expresses higher SULT1E1, paralleling HIF1α protein/mRNA owing to lower LDH activity. In addition, increase of MMP2/9 activities commenced tissue damage. However, chalcone and DAS significantly induced SULT1E1 gene/protein, and suppressed HIF1α expression, and MMP2/9 activities in rat tissues. Correlation of individual parameter statistics and group statistics of t-test suggest significant correlation of oxidative-stress (MDA) with SULT1E1 (p=0.006), HIF1α (p=0.006) protein-expression. The non-protein-thiols showed a negative correlation (p=0.001) with HIF1α. These two proteins and SULT1E1 mRNA expressions in human breast tumor were significantly higher (p<0.05) compared to the adjacent tissues. Pearson correlation data suggest, SULT1E1 is correlated with non-protein-thiols in different exposure groups. Conclusions: Breast cancers associate with SULT1E1, HIF1α and MMPs deregulations. We are reporting for the first time that higher SULT1E1-protein in advanced cancer, remain inactive in oxidative environment and may be re-activated in chalcone induced reducing-state. Moreover, DAS induced SULT1E1 mRNA expression augments its protein synthesis. Synergistic drug-effects commenced HIF1α and MMPs suppression. Further studies are necessary.