Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA.
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68918-6805, USA.
J Ovarian Res. 2024 May 4;17(1):94. doi: 10.1186/s13048-024-01421-4.
Genetic studies implicate the oncogenic transcription factor Forkhead Box M1 (FOXM1) as a potential therapeutic target in high-grade serous ovarian cancer (HGSOC). We evaluated the activity of different FOXM1 inhibitors in HGSOC cell models.
We treated HGSOC and fallopian tube epithelial (FTE) cells with a panel of previously reported FOXM1 inhibitors. Based on drug potency, efficacy, and selectivity, determined through cell viability assays, we focused on two compounds, NB-73 and NB-115 (NB compounds), for further investigation. NB compounds potently and selectively inhibited FOXM1 with lesser effects on other FOX family members. NB compounds decreased FOXM1 expression via targeting the FOXM1 protein by promoting its proteasome-mediated degradation, and effectively suppressed FOXM1 gene targets at both the protein and mRNA level. At the cellular level, NB compounds promoted apoptotic cell death. Importantly, while inhibition of apoptosis using a pan-caspase inhibitor rescued HGSOC cells from NB compound-induced cell death, it did not rescue FOXM1 protein degradation, supporting that FOXM1 protein loss from NB compound treatment is specific and not a general consequence of cytotoxicity. Drug washout studies indicated that FOXM1 reduction was retained for at least 72 h post-treatment, suggesting that NB compounds exhibit long-lasting effects in HGSOC cells. NB compounds effectively suppressed both two-dimensional and three-dimensional HGSOC cell colony formation at sub-micromolar concentrations. Finally, NB compounds exhibited synergistic activity with carboplatin in HGSOC cells.
NB compounds are potent, selective, and efficacious inhibitors of FOXM1 in HGSOC cells and are worthy of further investigation as HGSOC therapeutics.
遗传研究表明致癌转录因子叉头盒 M1（FOXM1）是高级别浆液性卵巢癌（HGSOC）的潜在治疗靶点。我们评估了不同 FOXM1 抑制剂在 HGSOC 细胞模型中的活性。
我们用一组先前报道的 FOXM1 抑制剂处理 HGSOC 和输卵管上皮（FTE）细胞。基于通过细胞活力测定确定的药物效力、功效和选择性，我们重点研究了两种化合物，NB-73 和 NB-115（NB 化合物），以进行进一步研究。NB 化合物通过靶向 FOXM1 蛋白促进其蛋白酶体介导的降解，强烈且选择性地抑制 FOXM1，对其他 FOX 家族成员的影响较小。NB 化合物通过靶向 FOXM1 蛋白来降低 FOXM1 的表达，从而促进其蛋白酶体介导的降解，并有效地抑制 FOXM1 基因靶标在蛋白质和 mRNA 水平上的表达。在细胞水平上，NB 化合物促进了细胞凋亡。重要的是，虽然使用泛半胱天冬酶抑制剂抑制凋亡挽救了 HGSOC 细胞免受 NB 化合物诱导的细胞死亡，但它并没有挽救 FOXM1 蛋白降解，这支持了 NB 化合物处理后 FOXM1 蛋白的丢失是特异性的，而不是细胞毒性的一般后果。药物洗脱研究表明，FOXM1 的减少在治疗后至少 72 小时内保持不变，这表明 NB 化合物在 HGSOC 细胞中具有持久的作用。NB 化合物以亚微摩尔浓度有效抑制二维和三维 HGSOC 细胞集落形成。最后，NB 化合物在 HGSOC 细胞中与卡铂表现出协同活性。
NB 化合物是 HGSOC 细胞中 FOXM1 的有效、选择性和有效的抑制剂，值得进一步研究作为 HGSOC 治疗药物。
