PO.ET09.08 · 实验与分子治疗
抗寄生虫药物作为卵巢癌潜在治疗药物的评估
Evaluation of anti-parasitic agents as potential therapeutics in ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
预计2025年卵巢癌将在美国夺去约13,000人的生命。目前的治疗选择仍然有限且往往疗效不足，凸显了对可能改善生存结局的替代疗法的需求。为探索此类可能性，我们筛选了两种抗寄生虫药物：ivermectin（IV）和fenbendazole（FZ）。这些药物据报道具有抗癌特性。两种药物均使用基于发光的CellTiter-Glo细胞活力检测试剂盒（Promega）在卵巢癌细胞系SKOV3和ES-2上进行了测试。既往研究表明，这些化合物可在某些癌细胞系和小鼠异种移植模型中抑制增殖并促进凋亡。FZ尤其被报道可改变MYC（一种参与癌细胞生长、增殖和存活的基因）的表达。利用开放获取的癌症数据库，我们从癌症基因组图谱（The Cancer Genomic Atlas）检索数据，发现卵巢癌患者中MYC高表达与生存率下降显著相关（p = 0.044）。我们的细胞活力检测揭示了细胞系依赖性的抗增殖反应。ES-2细胞在IV或FZ处理后表现出明显的剂量依赖性活力下降，而SKOV3细胞的敏感性相对较低。对于ES-2，IV在8、4、2和1 μM剂量下处理48小时后，活力分别为0.88%、4.91%、18.82%和78.97%；对于SKOV3，相应的活力分别为8.92%、56.62%、76.61%和100.0%。FZ产生了类似的趋势：ES-2在5、2.5、1.25和0.625 μM下的活力为6.97%、27.02%、50.52%和69.46%，而SKOV3的活力分别为17.32%、19.46%、20.49%和50.54%。IC50计算进一步凸显了这些差异。在SKOV3中，FZ的IC50（1.02 μM）低于IV的IC50（3.678 μM）。在ES-2中，两种药物产生了相似的IC50值（IV：2.5345 μM；FZ：2.3285 μM）。这些发现提示了这些抗寄生虫药物潜在的抗癌活性，并有待进一步测试其作为卵巢癌治疗候选药物的疗效。我们的实验室目前正在研究将这些药物与标准化疗药物以及其他已被证明能调节MYC的药物和其他新兴抗癌化合物联合使用，以提高卵巢癌患者的治疗疗效。
查看英文原文 English abstract
Ovarian cancer is projected to claim approximately 13,000 lives in the United States in 2025. Current treatment options remain limited and often insufficiently effective, underscoring the need for alternative therapeutics that may improve survival outcomes. To explore such possibilities, we screened two anti-parasitic drugs: ivermectin (IV) and fenbendazole (FZ). These drugs have been reported to exhibit anti-cancer properties. Both drugs were tested on the ovarian cancer cell lines SKOV3 and ES-2 using a luminescence-based CellTiter-Glo cell viability assay kit (Promega). Previous studies indicate that these compounds can inhibit proliferation and promote apoptosis in some cancer cell lines and mouse xenograft models. FZ in particular has been reported to alter the expression of MYC , a gene involved in cancer cell growth, proliferation, and survival. Using the open-access cancer database, we retrieved data from The Cancer Genomic Atlas and found that high MYC expression in ovarian cancer patients significantly correlates with decreased survival (p = 0.044). Our cell viability assays revealed cell line-dependent anti-proliferative responses. ES-2 cells displayed a clear dose-dependent decrease in viability following IV or FZ treatment, whereas SKOV3 cells were comparatively less sensitive. For ES-2, IV at 8, 4, 2, and 1 μM doses at 48-hour post-treatment, yielded viabilities of 0.88%, 4.91%, 18.82%, and 78.97%, respectively; for SKOV3, the corresponding viabilities were 8.92%, 56.62%, 76.61%, and 100.0%. FZ produced a similar trend: ES-2 viabilities at 5, 2.5, 1.25, and 0.625 μM were 6.97%, 27.02%, 50.52%, and 69.46%, while SKOV3 viabilities were 17.32%, 19.46%, 20.49%, and 50.54%, respectively. IC 50 calculations further highlighted these differences. In SKOV3, the IC 50 for FZ (1.02 μM) was lower than that for IV (3.678 μM). In ES-2, both drugs produced similar IC 50 values (IV: 2.5345 μM; FZ: 2.3285 μM). These findings suggest the potential anti-cancer activity of these anti-parasitic agents and further testing their efficacy as therapeutic candidates for ovarian cancer. Our laboratory is currently investigating the combination therapies involving these drugs with standard chemotherapeutics and other agents shown to modulate MYC and other emerging anti-cancer compounds to improve treatment efficacy for ovarian cancer patients.
利益披露 Disclosure
A. Ochoa Negrete, None..
A. Kankanala, None..
R. Basha, None.