SPL-108 可减轻输卵管卵巢癌的转移和化疗耐药性。

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2024-11-05 DOI:10.1016/j.tranon.2024.102168

Olivia D. Lara , Elke Van Oudenhove , Luiza Pereira , Selim Misirlioglu , Douglas A. Levine , Kari E. Hacker

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引用次数: 0

摘要

背景：克服转移和化疗耐药性的异质性机制将改善女性输卵管卵巢癌（TOC）患者的预后。CD44的表达已被证明与TOC的不良预后和晚期疾病有关。此外，研究还表明化疗耐药性与 CD44 通路之间存在联系。鉴于靶向 CD44 的治疗意义，本稿件研究了新型 CD44 调节剂 SPL-108 在 TOCs 中的生物效应：我们评估了 SPL-108 对具有不同 CD44 和 MDR1 表达的卵巢癌细胞系的化疗敏感性和迁移的影响。我们进行了体外实验（细胞活力测定、Western印迹分析、钙黄绿素AM荧光测定和迁移测定），以确定SPL-108在TOCs中的功能效应：Western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处理可明显减少OVCAR8、OVCAR5和OVCAR3细胞系中迁移细胞的数量，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，用 SPL-108 处理会导致 MDR1 底物钙黄绿素在 OVCAR5、OVCAR8 和 OVCAR3 细胞系中明显积累。在 MDR1 蛋白高表达的细胞系中，SPL-108 处理后可看到钙黄绿素的保留，而在缺乏 MDR1 表达的细胞中则看不到钙黄绿素的保留，这表明 SPL-108 可抑制 MDR1：结论：SPL-108治疗具有抗转移特性，可能在临床前TOC模型的化疗耐药性中发挥作用，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。

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SPL-108 mitigates metastasis and chemoresistance in tubo-ovarian carcinoma

Background

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.

Materials and Methods

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.

Findings

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.

Conclusions

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.

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.