SPL-108 mediates metastasis and chemoresistance in high-grade serous tubo-ovarian carcinoma

Abstract

Objectives: Overcoming chemoresistance will improve outcomes for all women with tubo-ovarian carcinomas. Mechanisms of chemoresistance are multifactorial and heterogeneous. ABCB1 (MDR1) represents one common resistance mechanism in tubo-ovarian carcinomas and is under the regulation of CD44. In the present study we examined the effects of a novel CD44 modulator, SPL-108, in a panel of ovarian cancer cell lines. Methods: We assessed chemosensitivity and migration effects of SPL-108 in a panel of ovarian cancer cell lines with (OVCAR5, OVCAR8, OVCAR3) and without (OVCAR4, CAOV3) 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. Results: Higher expression of CD44 was seen in OVCAR5 and OVCAR8 on Western Blot analysis. In transwell migration assay, treatment with SPL-108 decreased the number of migrating cells compared to control in OVCAR8 (mean ± SEM, 149.1 ± 22.8 vs 89.0 ± 16.5 cells, p=0.04), OVCAR5 (177.7 ± 15.4 vs 134.5 ± 14.7 cells, p=0.04) and OVCAR3 (111.2 ± 12.4 vs 50.5 ± 9.4 cells, p Conclusions: SPL-108 treatment has anti-metastatic properties and suppresses chemoresistance in preclinical models of ovarian cancer. Ongoing studies in animal models will help to guide the further clinical development of SPL-108. Download : Download high-res image (262KB) Download : Download full-size image