4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer.

Noor A Lokman,Anne M Macpherson,Martin K Oehler,Zoe K Price,Emily K Hawkins,Carmela Ricciardelli

doi:10.3390/cancers11081187

Abstract

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.

Highlights

Ovarian cancer is the most lethal gynaecological cancer and the fifth most common cause of cancer-related death among Western women [1]
We found that HAS2 (Figure 2b) and HAS3 (Figure 2c) but not HAS1
We showed that 4-MU alone and combined CBP and 4-MU treatments increased the level of apoptosis in chemosensitive primary cells compared to control treatment (Figure 3g)

Summary

Introduction

Ovarian cancer is the most lethal gynaecological cancer and the fifth most common cause of cancer-related death among Western women [1]. Current clinical practice for advanced ovarian cancer consists of de-bulking surgery followed by combined platinum and taxane-based chemotherapy. High grade serous ovarian cancers make up nearly 70% of ovarian cancers and are characterized by high initial chemosensitivity. 75% of patients relapse after treatment and subsequently develop resistance to platinum-based drugs [2]. Chemotherapy resistance is the major clinical challenge in ovarian cancer treatment and strategies that can overcome chemoresistance will greatly improve patient survival.

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