We have recently shown that the extracellular matrix molecule
hyaluronan (HA) plays a role in the development of
ovarian cancer chemoresistance. This present study determined if HA production is increased in
chemotherapy-resistant
ovarian cancers and if the HA inhibitor 4-methylubelliferone (4-MU) can overcome chemoresistance to the chemotherapeutic drug
carboplatin (CBP) and inhibit spheroid formation and the expression of cancer stem cell (CSC) markers. We additionally assessed whether 4-MU could inhibit in vivo invasion of chemoresistant primary
ovarian cancer cells in the chicken embryo chorioallantoic membrane (CAM) assay. The expression of the HA synthases HAS2 and HAS3 was significantly increased in chemoresistant compared to chemosensitive primary
ovarian cancer cells isolated from patient
ascites. 4-MU significantly inhibited HA production, cell survival, and spheroid formation of chemoresistant serous
ovarian cancer cells. In combination with CBP, 4-MU treatment significantly decreased
ovarian cancer cell survival and increased apoptosis of chemoresistant primary cells compared to CBP alone. 4-MU significantly reduced spheroid formation, expression of CSC markers ALDH1A1 and ABCG2 in primary cell spheroid cultures, and ALDH1 immunostaining in patient-derived tissue explant assays following treatment with CBP. Furthermore, 4-MU was very effective at inhibiting in vivo invasion of chemoresistant primary cells in CAM assays. Inhibition of HA is therefore a promising new strategy to overcome chemoresistance and to improve
ovarian cancer survival.