Department of Urology, University Hospital Zürich, University of Zürich, Laboratory for Urologic Oncology and Stem Cell Therapy, Zürich, Switzerland.
Department of Nuclear Medicine, University Hospital of Zürich, University of Zürich, Zürich, Switzerland.
Cancer Rep (Hoboken). 2021 Dec;4(6):e1418. doi: 10.1002/cnr2.1418. Epub 2021 May 19.
Dutasteride has been shown to increase expression of the prostate-specific membrane antigen (PSMA) in prostate cancer cells in previous in vitro studies. This 5-alpha-reductase inhibitor is commonly used for the treatment of symptomatic benign prostatic enlargement. The modulation of PSMA expression might affect PSMA-based prostate cancer imaging and therapy.
The purpose of this work was to further analyze concentration-dependent effects of Dutasteride on PSMA expression in a mouse xenograft model.
Four groups of mice bearing LNCaP xenografts were treated for 14 days with daily intraperitoneal injections of either vehicle control or different concentrations of Dutasteride (0.1, 1, 10 mg/kg). Total expression of PSMA, androgen receptor (AR), and caspase-3 protein was analyzed using immunoblotting (WES). In addition, PSMA, cleaved caspase-3 and Ki-67 expression was assessed and quantified by immunohistochemistry. Tumor size was measured by caliper on day 7 and 14, tumor weight was assessed following tissue harvesting. The mean PSMA protein expression in mice increased significantly after treatment with 1 mg/kg (10-fold) or 10 mg/kg (sixfold) of Dutasteride compared to vehicle control. The mean fluorescence intensity significantly increased by daily injections of 0.1 mg/kg Dutasteride (1.6-fold) as well as 1 and 10 mg/kg Dutasteride (twofold). While the reduction in tumor volume following treatment with high concentrations of 10 mg/kg Dutasteride was nonsignificant, no changes in AR, caspase-3, cleaved caspase-3, and Ki-67 expression were observed.
Short-term Dutasteride treatments with concentrations of 1 and 10 mg/kg significantly increase the total PSMA protein expression in a mouse LNCaP xenograft model. PSMA fluorescence intensity increases significantly even using lower daily concentrations of 0.1 mg/kg Dutasteride. Further investigations are needed to elucidate the impact of Dutasteride treatment on PSMA expression in patients.
先前的体外研究表明，度他雄胺可增加前列腺癌细胞中前列腺特异性膜抗原（PSMA）的表达。这种 5α-还原酶抑制剂常用于治疗有症状的良性前列腺增生。PSMA 表达的调节可能会影响基于 PSMA 的前列腺癌成像和治疗。
本研究旨在进一步分析度他雄胺在 LNCaP 异种移植模型中浓度依赖性对 PSMA 表达的影响。
四组携带 LNCaP 异种移植物的小鼠每天接受腹腔内注射溶剂对照或不同浓度度他雄胺（0.1、1、10mg/kg）治疗 14 天。使用免疫印迹（WES）分析 PSMA、雄激素受体（AR）和半胱氨酸天冬氨酸蛋白酶-3（caspase-3）蛋白的总表达。此外，通过免疫组织化学评估和量化 PSMA、裂解 caspase-3 和 Ki-67 的表达。第 7 天和第 14 天通过卡尺测量肿瘤大小，组织收获后评估肿瘤重量。与溶剂对照组相比，用 1mg/kg（10 倍）或 10mg/kg（6 倍）度他雄胺处理后，小鼠 PSMA 蛋白表达的平均值显著增加。用 0.1mg/kg 度他雄胺（1.6 倍）以及 1 和 10mg/kg 度他雄胺（2 倍）每日注射，平均荧光强度显著增加。尽管用高浓度 10mg/kg 度他雄胺治疗后肿瘤体积减少不显著，但未观察到 AR、caspase-3、裂解 caspase-3 和 Ki-67 表达的变化。
在 LNCaP 异种移植模型中，用 1 和 10mg/kg 的度他雄胺短期治疗可显著增加总 PSMA 蛋白表达。即使使用 0.1mg/kg 度他雄胺的较低每日浓度，PSMA 荧光强度也会显著增加。需要进一步研究来阐明度他雄胺治疗对患者 PSMA 表达的影响。
