Evaluation of the effect of the new methoxy-stilbenes on expression of receptors and enzymes involved in estrogen synthesis in cancer breast cells

Abstract

Our previous study showed that the new synthetic methoxy-stilbenes, 3,4,2′-trimethoxy-trans-stilbene (3MS), 3,4,2′,4′-tetramethoxy-trans-stilbene (4MS), and 3,4,2′,4′,6′-pentamethoxy-trans-stilbene (5MS), modulate the constitutive expression of enzymes and receptors involved in estrogen metabolism in breast immortalized epithelial MCF10 cells. In this study, we evaluated the effect of 3MS, 4MS, and 5MS in comparison to resveratrol activity in MCF7 estrogen-dependent and MDA-MB-231 estrogen-independent breast cancer cell lines. 3MS similarly to resveratrol reduced the expression of estrogen receptor α in MCF7 cells. However, in these cells, 5MS reduced the most CYP19, the gene encoding aromatase, at mRNA transcript level. In contrast, in the MDA-MB-231 cells, the most efficient inhibitor of CYP19 expression was 3MS, reducing the level of its protein by ~ 25%. This stilbene also inhibited the aromatase activity in a recombinant protein system with IC50 value ~ 85 µM. Treatment with the methoxy-stilbenes reduced the level of estradiol in culture medium. The most significant reduction was exerted by 3MS. None of the tested stilbenes including resveratrol changed significantly the expression of AhR, although CYP1A1 protein level was slightly reduced in MDA-MB-231 cells, while CYP1B1 expression was increased in these cells as a result of treatment with 3MS, but only at the transcript level. Overall, these results show weak or moderate effect of the new methoxy-stilbenes on the expression of key proteins involved in estrogens metabolism in cancer breast cells. However, the reduced CYP19 expression and activity upon 3MS treatment in metastatic MDA-MB-231 cells require the further studies.

Effect of methoxy stilbenes—analogs of resveratrol—on the viability and induction of cell cycle arrest and apoptosis in human myeloid leukemia cells

“…Our previous studies also showed that 3,5,4ʹ-tri-MS caused a massive accumulation of cells at the G2/M phase of the cell cycle and increased the apoptosis rate related to p53 induction in rat C6 glioma cells [13]. In addition, synthetic 3,4,2′-tri-MS, 3,4,2′,4′-tetra-MS, and 3,4,2′,4′,6′-penta-MS modulated the constitutive expression of enzymes and receptors involved in estrogen metabolism in breast normal and cancer cells more efficiently than RSV [14,15]. Cytochromes P450 1A1 and 1B1 are crucial for the metabolism of estrogen to their reactive electrophilic forms.…”

Chinese Medicines Improve Perimenopausal Symptoms Induced by Surgery, Chemoradiotherapy, or Endocrine Treatment for Breast Cancer

“…Promoters I.3 and II are the major promoters directing aromatase expression in breast cancer, and genistein may inhibit the activities of promoters I.3 and II for CYP19 regulation (Chen et al, 1999 ). A study showed that a methoxy derivative of resveratrol, 3MS, could efficiently inhibit the expression of aromatase protein encoded by CYP19 in MDA-MB- 231 cells (Licznerska et al, 2017 ). The standard GBE (EGb 761) significantly inhibited aromatase activity and reduced the expression of CYP19 mRNA and CYP19 promoter I.3 and PII (Park et al, 2016 ).…”

Combretastatin analogues in cancer biology: A prospective view

“…They reduced receptor expression and also suppressed the expression of the CYP19 gene more effectively than resveratrol. The synthetic stilbenes were more powerful inhibitors of cell proliferation and promoters of apoptosis . Over a decade ago Saberi et al synthesises several 1‐[(benzofuran‐2‐yl)phenylmethyl]‐pyridine, ‐imidazole, and ‐triazole compounds and noted that the 6‐methoxy‐ and 6‐hydroxy‐substituted benzofuran derivatives were highly effective inhibitors of CYP19 far more effective and selective than the parent compound; overall the effects were comparable with that of anastrozole.…”

“…The synthetic stilbenes were more powerful inhibitors of cell proliferation and promoters of apoptosis. 37 Over a decade ago Saberi et al 38 synthesises several 1-[(benzofuran-2-yl) phenylmethyl]-pyridine, -imidazole, and -triazole compounds and noted that the 6-methoxy-and 6-hydroxysubstituted benzofuran derivatives were highly effective inhibitors of CYP19 far more effective and selective than the parent compound; overall the effects were comparable with that of anastrozole. Methoxy substitution of the coumarin core produces potent aromatase inhibitors, possibly not comparable in bioactivity to anastrozole or letrozole, but distinctly more potent than aminoglutethimide.…”