PO.ET02.10 · 实验与分子治疗
咪康唑通过p53介导的通路诱导前列腺癌细胞的细胞周期停滞和凋亡：一种药物重定位策略
Miconazole induces cell cycle arrest and apoptosis in prostate cancer cells via a p53-mediated pathway: A Drug repurposing strategy
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摘要 Abstract
中文摘要
研究目的：本研究探索将FDA批准的抗真菌药物重新定位作为前列腺癌潜在疗法。
背景：前列腺癌仍是美国男性癌症相关死亡的第二大原因。美国癌症协会估计2025年将有约313,780例新发病例和35,770例前列腺癌死亡。目前的治疗手段，包括放疗、化疗、激素治疗及其他新兴模式，常伴随长期不良反应，凸显了对新型治疗策略的需求。
步骤：我们使用CCK-8、集落形成、侵袭和迁移实验筛选抗真菌药物，以确定对前列腺癌细胞最有效的化合物。对先导命中分子咪康唑进一步评估其促凋亡和细胞周期调控作用，使用共聚焦和扫描电子显微镜、流式细胞术和Western印迹。进行蛋白质组学分析和通路富集分析以鉴定关键分子靶点。通过分子对接评估咪康唑的结合亲和力。
结果：与其他抗真菌药物相比，咪康唑显著抑制前列腺癌细胞的增殖、克隆形成能力、侵袭和迁移特性。机制研究揭示，通过下调cyclin D3、CDK2、CDK4和PCNA引起G0/G1细胞周期停滞，并通过上调p53、p21、p27、cl-PARP、cl-caspase-3，同时抑制PARP-1和caspase-3诱导凋亡。此外，蛋白质组学分析显示咪康唑显著调控了许多负责细胞周期停滞和凋亡的蛋白质。分子对接表明，咪康唑与PARP1（-8.97 kcal/mol）和cyclin D3（-8.50 kcal/mol）表现出强结合亲和力，与CDK4（-7.19 kcal/mol）和CDK2（-6.15 kcal/mol）表现出中等结合亲和力，与PCNA（-5.14 kcal/mol）、TP53（-4.89 kcal/mol）和CDKN1B（-3.50 kcal/mol）表现出较低结合亲和力。与caspase-3未发现显著结合（+65.04 kcal/mol）。
结论：这些发现凸显咪康唑作为前列腺癌治疗药物重定位的有希望的候选药物，为未来的联合策略提供了潜在基础。
关键词：前列腺癌；重定位；抗真菌药物；咪康唑；凋亡；蛋白质组学
查看英文原文 English abstract
Purpose of the study: This study explores the repurposing of FDA-approved antifungal drugs as potential therapeutics for prostate cancer.
Background: Prostate cancer remains the second leading cause of cancer-related deaths among men in the United States. The American Cancer Society estimated about 313,780 new cases and 35,770 deaths projected from prostate cancer in 2025. Current treatments, including radiation, chemotherapy, hormone therapy, and other emerging modalities, are often associated with long-term adverse effects, underscoring the need for novel therapeutic strategies.
Procedures: We screened antifungal drugs using CCK-8, colony formation, invasion, and migration assays to identify the most effective compound against prostate cancer cells. The lead hit molecule, miconazole, was further evaluated for its pro-apoptotic and cell cycle regulatory effects using confocal and scanning electron microscopy, flow cytometry, and Western blotting. Proteomic profiling and pathway enrichment analyses were performed to identify key molecular targets. The binding affinities of miconazole were evaluated via molecular docking.
Results: Miconazole significantly inhibited prostate cancer cell proliferation, clonogenic capacity, invasion, and migration properties compared to other antifungal agents. Mechanistic studies revealed G0/G1 cell cycle arrest through downregulation of cyclin D3, CDK2, CDK4, and PCNA, and induction of apoptosis via upregulation of p53, p21, p27, cl-PARP, cl-caspase-3, alongside suppression of PARP-1 and caspase-3. Further, proteomic analysis revealed that miconazole significantly regulated many proteins that are responsible for cell cycle arrest and apoptosis. Molecular docking demonstrated that miconazole exhibited strong binding affinities with PARP1 (-8.97 kcal/mol) and cyclin D3 (-8.50 kcal/mol), moderate binding affinities with CDK4 (-7.19 kcal/mol) and CDK2 (-6.15 kcal/mol), and lower binding affinities with PCNA (-5.14 kcal/mol), TP53 (-4.89 kcal/mol), and CDKN1B (-3.50 kcal/mol). No significant binding was found with caspase-3 (+65.04 kcal/mol).
Conclusions: These findings highlight miconazole as a promising candidate for drug repurposing in prostate cancer therapy, offering a potential foundation for future combination strategies.
Keywords: Prostate cancer; Repurposing; Antifungal drugs; Miconazole; Apoptosis; Proteomics
利益披露 Disclosure
E. Ghali, None..
L. Shim, None..
R. Tiwari, None..
R. Baru, None..
A. Dhasmana, None..
C. Ryan Jisoo, None..
S. Yun Jung, None..
V. K. Kashyap, None..
N. Chauhan, None..
S. C. Chauhan, None..
M. M. Yallapu, None.