Sesamol Epigenetically Induces Estrogen Receptor α Re-expression by Upregulating miR-370-3p in Estrogen Receptor α-Negative Breast Cancer

Abstract

Due to lack of estrogen receptor α (ERα, gene name: ESR1), ERα-negative breast carcinoma is insensitive to endocrine therapy, and restoration of ERα has become a promising strategy for ERα-negative breast cancer treatment. Sesamol, a naturally occurring phenolic compound, is usually extracted from sesame seeds. Previous investigations have unmasked its antioxidant and anti-inflammation properties. In this study, sesamol induced ERα functional re-expression followed by upregulation of its downstream pS2 and GREB1 genes in ERα-negative breast carcinoma. Moreover, it endowed responsiveness of ERα-negative breast carcinoma to the endocrine treatment drug 4-hydroxytamoxifen without influencing the viability of normal human umbilical vein endothelial cells. Mechanistically, sesamol induced ESR1 gene promoter demethylation by downregulating the expression of the DNA methyltransferases DNMT3A and DNMT3B, without affecting DNMT1. Moreover, the non-coding RNA miR-370-3p directly targeted DNMT3A and DNMT3B mRNA, and its expression increased upon treatment with sesamol. Artificial abrogation of miR-370-3p expression with an antagomir abolished the inhibition of DNMT3A and DNMT3B expression by sesamol, resulting in a fallback in ERα reactivation. In mice, sesamol significantly induced ERα re-expression via miR-370-3p-mediated downregulation of DNMT3A and DNMT3B. Sesamol may be a safe and effective option for clinical adjuvant therapy in patients with ERα-negative breast cancer.

Synchronizing In Silico, In Vitro, and In Vivo Studies for the Successful Nose to Brain Delivery of an Anticancer Molecule

“…The EE % values of sesamol in both SLNs and PNs were in the range from 40.07 ± 0.76 to 66.09 ± 0.92. These results were satisfying with respect to a small hydrophilic cargo like sesamol that can easily leak out to the surrounding aqueous environment during preparation . Additionally, there was a significant increase ( p < 0.05) regarding the loaded amount of sesamol/100 mg of carrier in the case of PNs (from 43.51 ± 0.83 μmol to 67.04 ± 0.5 μmol) over SLNs (from 6.71 ± 0.09 μmol to 9.58 ± 0.1 μmol).…”

“…It is clear that both of the loaded nanoparticles achieved a higher cytotoxic effect than pure sesamol, indicating the efficient uptake of nanoparticles by malignant cells causing better intracellular internalization of sesamol and subsequent potentiation of its effect. 4 The differences from pure sesamol were statistically significant at p < 0.05. Additionally, a carrier-mediated cytotoxic effect was noticed in the case of GMS-SLNs, inferred from the low IC 50 score of plain GMS-SLNs (179.67 ± 16.06 μM).…”

“…These results were satisfying with respect to a small hydrophilic cargo like sesamol that can easily leak out to the surrounding aqueous environment during preparation. 4 Additionally, there was a significant increase (p < 0.05) regarding the loaded amount of sesamol/100 mg of carrier in the case of PNs (from 43.51 ± 0.83 μmol to 67.04 ± 0.5 μmol) over SLNs (from 6.71 ± 0.09 μmol to 9.58 ± 0.1 μmol). This might be again related to the relatively hydrophilic nature of sesamol, which has a lower affinity toward the highly hydrophobic lipid matrix.…”

“…By virtue of its small size and low molecular weight (138.12 g/mole), it could be inserted in the DNA grooves, leading to helix unwinding and cell apoptosis . To the best of our knowledge, its cytotoxic effect has been tested on hepatic, breast, lung, skin, and colon cancers but not on any type of brain cancers. Unfortunately, the physicochemical characters of sesamol as a small molecule with adequate aqueous solubility (38.8 mg/mL) and an almost balanced partition coefficient value (1.29) allow its even biodistribution throughout the body and absence of specific affinity toward a pathological site/tissue .…”

An Insight Into Sesamol: Pharmacological Activities, and Future Research Prospects

“…Recently, sesamol has been documented to found that sesame phytoestrogen lignanscan stimulate testosterone aromatization to estradiol, or convert it to Dihydrotestosterone. High level intake of liquorice root extract or sesame oil caused hormonal disturbance and decreases sperm count [61].…”