Abstract
4-Methylumbelliferone (4-MU), a hyaluronan (HA) synthesis inhibitor, has antitumor activity in cancer cells. However, few studies have focused on its effects on ovarian cancer. The aim of this study was to investigate the effects of 4-MU on ovarian cancer and to elucidate its mechanism of action. The HRA human ovarian serous adenocarcinoma cell line was used in this study. The effects of 4-MU on cell proliferation, migration, and invasion were determined by using in vitro assays as well as an in vivo rat peritoneal carcinomatosis model. The expression of HA synthase (HAS), CD44 HA receptor, vascular endothelial growth factor (VEGF), and thymidine phosphorylase (TP) mRNA in HRA cells was analyzed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). 4-MU administration inhibited the growth of peritoneal tumors and significantly prolonged survival. In vitro experiments showed that 4-MU inhibited HRA cell proliferation in a dose-dependent manner, while it did not affect HRA cell invasion and migration. 4-MU significantly decreased TP mRNA expression in HRA cells. On the other hand, since HAS2, CD44, and VEGF endogenous mRNA expression levels were very low in HRA cells, it was impossible to evaluate the effect of 4-MU treatment. These results suggest that 4-MU exerts its antitumor effect on ovarian cancer through suppressing TP expression.
Highlights
Epithelial ovarian cancer is the most lethal malignancy in women because it is usually diagnosed at the severe peritonitis carcinomatosa advanced stage of the disease
The post-mortem examination showed that their intraperitoneal tumors were much smaller than those in the control rats even though 4-MU administration was discontinued after day 14 (Figure 1C)
Since HAS2, CD44, and vascular endothelial growth factor (VEGF) endogenous mRNA expression levels were very low in HRA cells their expression levels were high in U373MG human astrocytoma cells [18] and SH-SY5Y human neuroblastoma cells [20], it was impossible to evaluate the effect of 4-MU treatment
Summary
Epithelial ovarian cancer is the most lethal malignancy in women because it is usually diagnosed at the severe peritonitis carcinomatosa advanced stage of the disease. Cytoreductive surgery followed by adjuvant chemotherapy is commonly recommended as the primary treatment for advanced (stage III/IV) epithelial ovarian cancer. The combination of a taxane and carboplatin is used as first-line chemotherapy [2]. Chemotherapy plays an important role in ovarian cancer treatment. Some patients with advanced ovarian cancer develop chemoresistance, which makes it difficult to prevent the development of peritonitis carcinomatosa, leading to reduced quality of life and a poor prognosis. Since the effects of the available treatments for ovarian cancer are restricted, it is necessary to develop new drugs
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