Lara Olivia D, Van Oudenhove Elke, Pereira Luiza, Misirlioglu Selim, Levine Douglas A, Hacker Kari E
Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Division of Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Transl Oncol. 2025 Jan;51:102168. doi: 10.1016/j.tranon.2024.102168. Epub 2024 Nov 5.
Overcoming the heterogeneous mechanisms of metastasis and chemoresistance will improve outcomes for women with tubo-ovarian carcinomas (TOCs). CD44 expression has been shown to be associated with poor prognosis and advanced disease in TOCs. In addition, studies have shown a link between chemoresistance and CD44 pathways. Given the therapeutic implications of targeting CD44, this manuscript examines the biologic effects of a novel CD44 modulator, SPL-108, in TOCs.
We assessed the effects of SPL-108 on chemosensitivity and migration in a panel of ovarian cancer cell lines with varied CD44 and MDR1 expression. In vitro experiments (cell viability assay, Western blot analysis, Calcein AM fluorescence assay, and migration assay) were carried out to determine the functional effects of SPL-108 in TOCs.
Ovarian cancer cell lines OVCAR5 and OVCAR8 expressed higher protein levels of CD44 as demonstrated through Western Blot analysis. SPL-108 treatment significantly decreased the number of migrating cells in OVCAR8, OVCAR5 and OVCAR3 cell lines and migratory response was independent of CD44 expression. Treatment with SPL-108 led to significant accumulation of the MDR1 substrate Calcein in OVCAR5, OVCAR8 and OVCAR3 cells lines compared to verapamil treated positive control cells. Retention of Calcein after SPL-108 treatment was seen in cell lines with high MDR1 protein expression and no Calcein retention was seen in cells lacking MDR1 expression, suggesting SPL-108 inhibits MDR1.
SPL-108 treatment has anti-metastatic properties and may play a role in chemoresistance in preclinical models of TOCs independent of CD44 expression. Ongoing in vitro and in vivo studies will help guide further clinical development of SPL-108.
克服转移和化疗耐药的异质性机制将改善输卵管卵巢癌（TOC）女性患者的治疗结果。已表明CD44表达与TOC的不良预后和疾病进展相关。此外，研究显示化疗耐药与CD44通路之间存在联系。鉴于靶向CD44的治疗意义，本手稿研究了新型CD44调节剂SPL-108在TOC中的生物学效应。
我们评估了SPL-108对一组具有不同CD44和MDR1表达的卵巢癌细胞系的化疗敏感性和迁移的影响。进行了体外实验（细胞活力测定、蛋白质印迹分析、钙黄绿素AM荧光测定和迁移测定）以确定SPL-108在TOC中的功能作用。
通过蛋白质印迹分析表明，卵巢癌细胞系OVCAR5和OVCAR8表达较高水平的CD44蛋白。SPL-108处理显著减少了OVCAR8、OVCAR5和OVCAR3细胞系中的迁移细胞数量，并且迁移反应与CD44表达无关。与维拉帕米处理的阳性对照细胞相比，SPL-108处理导致OVCAR5、OVCAR8和OVCAR3细胞系中MDR1底物钙黄绿素的显著积累。在具有高MDR1蛋白表达的细胞系中观察到SPL-108处理后钙黄绿素的保留，而在缺乏MDR1表达的细胞中未观察到钙黄绿素的保留，表明SPL-108抑制MDR1。
SPL-108处理具有抗转移特性，并且可能在TOC临床前模型的化疗耐药中发挥作用，且与CD44表达无关。正在进行的体外和体内研究将有助于指导SPL-108的进一步临床开发。
