Vini Ravindran, Jaikumar Vishnu Sunil, Remadevi Viji, Ravindran Swathy, Azeez Juberiya M, Sasikumar Anjana, Sundaram Shankar, Sreeja Sreeharshan
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India.
Research Centre, University of Kerala, Thiruvananthapuram, India.
Phytother Res. 2023 Oct;37(10):4504-4521. doi: 10.1002/ptr.7919. Epub 2023 Jun 21.
27-hydroxycholesterol (27-HC) is an oxysterol that acts as an endogenous selective estrogen receptor modulator (SERM), and its adverse effects on breast cancer via the estrogen receptor (ER) have provided new insights into the pathology of cholesterol-linked breast cancer. Our earlier in vitro experiments showed that the methanolic extract of pomegranate could exhibit SERM properties and compete with 27-HC. The major constituents of pomegranate are ellagitannins and ellagic acid, which are converted into urolithins by the colonic microbiota. In recent years, urolithins, especially urolithin A (UA) and urolithin B (UB), have been reported to have a plethora of advantageous effects, including antiproliferative and estrogenic activities. In this study, we attempted to determine the potential of urolithins in antagonizing and counteracting the adverse effects of 27-HC in breast cancer cells. Our findings suggested that UA had an antiproliferative capacity and attenuated the proliferative effects of 27-HC, resulting in subsequent loss of membrane potential and apoptosis in breast cancer cells. Further, UA induced estrogen response element (ERE) transcriptional activity and modulated estrogen-responsive genes, exhibiting a SERM-like response concerning receptor binding. Our in vivo hollow fiber assay results showed a loss of cell viability in breast cancer cells upon UA consumption, as well as a reduction in 27-HC-induced proliferative activity. Additionally, it was shown that UA did not induce uterine proliferation or alter blood biochemical parameters. Based on these findings, we can conclude that UA has the potential to act as a potent estrogen receptor alpha (ERα) modulator and 27-HC antagonist. UA is safe to consume and is very well tolerated. This study further opens up the potential of UA as ER modulator and its benefits in estrogen-dependent tissues.
27-羟基胆固醇（27-HC）是一种氧化甾醇，作为内源性选择性雌激素受体调节剂（SERM）发挥作用，其通过雌激素受体（ER）对乳腺癌产生的不良影响为胆固醇相关乳腺癌的病理学研究提供了新的见解。我们早期的体外实验表明，石榴甲醇提取物可表现出SERM特性并与27-HC竞争。石榴的主要成分是鞣花单宁和鞣花酸，它们可被结肠微生物群转化为尿石素。近年来，尿石素，尤其是尿石素A（UA）和尿石素B（UB），已被报道具有多种有益作用，包括抗增殖和雌激素活性。在本研究中，我们试图确定尿石素在拮抗和抵消27-HC对乳腺癌细胞不良影响方面的潜力。我们的研究结果表明，UA具有抗增殖能力，并减弱了27-HC的增殖作用，导致乳腺癌细胞膜电位随后丧失并发生凋亡。此外，UA诱导雌激素反应元件（ERE）转录活性并调节雌激素反应基因，在受体结合方面表现出类似SERM的反应。我们的体内中空纤维试验结果表明，摄入UA后乳腺癌细胞的细胞活力丧失，同时27-HC诱导的增殖活性降低。此外，研究表明UA不会诱导子宫增殖或改变血液生化参数。基于这些发现，我们可以得出结论，UA有潜力作为一种有效的雌激素受体α（ERα）调节剂和27-HC拮抗剂。UA食用安全且耐受性良好。本研究进一步揭示了UA作为ER调节剂的潜力及其在雌激素依赖性组织中的益处。
