Steib Anita, Pohóczky Krisztina, Tóth Norbert, Kormos Viktória, Kun József, Kálai Tamás, Mangel László, Mátyus Péter, Helyes Zsuzsanna
Department of Pharmacology and Pharmacotherapy, Medical School & Centre for Neuroscience, University of Pécs, Pécs, Hungary.
Eötvös Loránd Research Network, Chronic Pain Research Group, Pécs, Hungary.
Pharmacol Res Perspect. 2025 Oct;13(5):e70173. doi: 10.1002/prp2.70173.
The current treatments for advanced prostate adenocarcinoma (PAC) include the androgen receptor antagonist enzalutamide and docetaxel-based chemotherapy. Elevated monoamine oxidase-A (MAO-A) mRNA expression and activity in tumorous prostate positively correlate with disease progression and therapy resistance. While MAO-B mRNA expression was also demonstrated in PAC cell lines, its role remained unclear. Therefore, this study evaluates the effects of the irreversible MAO-B inhibitor selegiline and rasagiline and their combinations with conventional therapies on androgen-insensitive (PC-3, DU145) and androgen-sensitive (22Rv1, LNCaP, VCaP) PAC cell lines. MAO activity was determined by the MAO-Glo luminescence assay, viability by the ATP-based chemiluminescence method, proliferation by the Luna-II automated cell counter, and mRNA expressions by RT-qPCR. MAO-B mRNA was stably expressed by all PAC cell lines, with the highest expression in 22Rv1 and LNCaP cells. Selegiline reduced MAO-B activity by 75%-80% and decreased cell counts by 40%-50% at 100 μM in PC-3 and 22Rv1 cells. Selegiline concentration-dependently inhibited cell proliferation (100 μM-10 mM) and reduced viability (1-10 mM) similar to rasagiline in all cell lines. Combination with enzalutamide in 22Rv1, and with docetaxel in PC-3 demonstrated potentiating and additive effects, respectively. Selegiline reduced FOXA1 and GLUT1 mRNA expressions related to cancer progression and metabolism in both cell lines, increased the apoptosis-related BAX in PC-3, and decreased AR, EGFR, and SNAI2 in 22Rv1 linked to proliferation and metastasis. These findings suggest potential for selegiline repurposing in both androgen-sensitive and -insensitive PAC therapy by promoting apoptosis and inhibiting cancer growth and survival signals, respectively.
晚期前列腺腺癌（PAC）的当前治疗方法包括雄激素受体拮抗剂恩杂鲁胺和基于多西他赛的化疗。前列腺肿瘤中升高的单胺氧化酶A（MAO-A）mRNA表达和活性与疾病进展及治疗抗性呈正相关。虽然在PAC细胞系中也证实了MAO-B mRNA表达，但其作用仍不清楚。因此，本研究评估不可逆MAO-B抑制剂司来吉兰和雷沙吉兰及其与传统疗法联合使用对雄激素不敏感（PC-3、DU145）和雄激素敏感（22Rv1、LNCaP、VCaP）PAC细胞系的影响。通过MAO-Glo发光测定法测定MAO活性，通过基于ATP的化学发光法测定活力，通过Luna-II自动细胞计数器测定增殖，并通过RT-qPCR测定mRNA表达。所有PAC细胞系均稳定表达MAO-B mRNA，在22Rv1和LNCaP细胞中表达最高。在PC-3和22Rv1细胞中，司来吉兰在100μM时将MAO-B活性降低75%-80%，并使细胞计数减少40%-50%。司来吉兰在所有细胞系中浓度依赖性地抑制细胞增殖（100μM-10mM）并降低活力（1-10mM），与雷沙吉兰相似。在22Rv1中与恩杂鲁胺联合使用，在PC-3中与多西他赛联合使用分别显示出增强和相加作用。司来吉兰降低了两个细胞系中与癌症进展和代谢相关的FOXA1和GLUT1 mRNA表达，增加了PC-3中与凋亡相关的BAX，并降低了22Rv1中与增殖和转移相关的AR、EGFR和SNAI2。这些发现表明，司来吉兰分别通过促进凋亡和抑制癌症生长及存活信号，在雄激素敏感和不敏感的PAC治疗中具有重新利用的潜力。
