Carranza-Aranda Ahtziri Socorro, Santerre Anne, Segura-Cabrera Aldo, Cárdenas-Vargas Albertina, Martínez-Velázquez Moisés, Hernández-Gutiérrez Rodolfo, Herrera-Rodríguez Sara Elisa
Medical and Pharmaceutical Biotechnology Unit, Center for Research and Assistance in Technology and Design of the State of Jalisco A.C., 44270, Guadalajara, Jalisco, Mexico.
Department of Cellular and Molecular Biology, Biological and Agricultural Sciences Campus, University of Guadalajara, 45221, Zapopan, Jalisco, Mexico.
Curr Mol Pharmacol. 2024;17:e18761429350210. doi: 10.2174/0118761429350210250102131611.
Androgen receptor mutations, particularly T877A and W741L, promote prostate cancer (PCa). The main therapies against PCa use androgen receptor (AR) antagonists, including Bicalutamide; but these drugs lose their effectiveness over time. Chrysin is a flavonoid with several biological activities, including antitumoral properties; however, its potential as an antiandrogen must be explored.
The present study aimed to characterize and compare the molecular interactions of chrysin with wild-type and mutated ARs and their cytotoxic effect in an in vitro model of PCa.
The affinities and molecular interactions of Bicalutamide and chrysin for the wild-type and mutated forms of AR were assessed by molecular docking. The MTT assay was used to evaluate the cytotoxic effect of these ligands on the DU-145 (T877A) and PC3 (W741L) PCa cell lines and on non-tumoral RWPE-1 cells.
The molecular dockings predicted a higher affinity of chrysin for the mutated AR than the wild-type AR (WT-AR); meanwhile, Bicalutamide presented a higher affinity for WT-AR. The amino acid residues involved in molecular interactions within the binding site of these receptors changed according to the ligands and AR variants, affecting their affinity scores and biological effects (agonist/antagonists). Chrysin exerted a specific cytotoxic effect against the PCa tumoral cells but none against the non-tumoral cells. In contrast, Bicalutamide showed potent cytotoxicity against all cell lines.
This study evidences the potential antiandrogen effect of chrysin on mutated AR and specific cytotoxicity against PCa cells, suggesting that this flavonoid could be considered for PCa therapy.
雄激素受体突变，尤其是T877A和W741L，会促进前列腺癌（PCa）的发生。针对PCa的主要治疗方法使用雄激素受体（AR）拮抗剂，包括比卡鲁胺；但这些药物会随着时间推移失去疗效。白杨素是一种具有多种生物活性的黄酮类化合物，包括抗肿瘤特性；然而，其作为抗雄激素的潜力仍有待探索。
本研究旨在表征和比较白杨素与野生型和突变型AR的分子相互作用，以及其在PCa体外模型中的细胞毒性作用。
通过分子对接评估比卡鲁胺和白杨素对野生型和突变型AR的亲和力及分子相互作用。采用MTT法评估这些配体对DU-145（T877A）和PC3（W741L）PCa细胞系以及非肿瘤性RWPE-1细胞的细胞毒性作用。
分子对接预测白杨素对突变型AR的亲和力高于野生型AR（WT-AR）；同时，比卡鲁胺对WT-AR具有更高的亲和力。这些受体结合位点内参与分子相互作用的氨基酸残基会根据配体和AR变体而变化，影响它们的亲和力得分和生物学效应（激动剂/拮抗剂）。白杨素对PCa肿瘤细胞具有特异性细胞毒性作用，但对非肿瘤细胞无此作用。相比之下，比卡鲁胺对所有细胞系均显示出强效细胞毒性。
本研究证明了白杨素对突变型AR具有潜在的抗雄激素作用以及对PCa细胞的特异性细胞毒性，表明这种黄酮类化合物可考虑用于PCa治疗。
