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Objective@#Fenbendazole (FZ) has potential anti-cancer effects, but its poor water solubility limits its use for cancer therapy. In this study, we investigated the anti-cancer effect of FZ with different drug delivery methods on epithelial ovarian cancer (EOC) in both in vitro and in vivo models. @*Methods@#EOC cell lines were treated with FZ and cell proliferation was assessed. The effect of FZ on tumor growth in cell line xenograft mouse model of EOC was examined according to the delivery route, including oral and intraperitoneal administration. To improve the systemic delivery of FZ by converting fat-soluble drugs to hydrophilic, we prepared FZ-encapsulated poly(D,L-lactide-co-glycolide) acid (PLGA) nanoparticles (FZ-PLGA-NPs). We investigated the preclinical efficacy of FZ-PLGA-NPs by analyzing cell proliferation, apoptosis, and in vivo models including cell lines and patient-derived xenograft (PDX) of EOC. @*Results@#FZ significantly decreased cell proliferation of both chemosensitive and chemoresistant EOC cells. However, in cell line xenograft mouse models, there was no effect of oral FZ treatment on tumor reduction. When administered intraperitoneally, FZ was not absorbed but aggregated in the intraperitoneal space. We synthesized FZ-PLGA-NPs to obtain water solubility and enhance drug absorption. FZ-PLGA-NPs significantly decreased cell proliferation in EOC cell lines. Intravenous injection of FZ-PLGA-NP in xenograft mouse models with HeyA8 and HeyA8-MDR significantly reduced tumor weight compared to the control group. FZ-PLGA-NPs showed anti-cancer effects in PDX model as well. @*Conclusion@#FZ-incorporated PLGA nanoparticles exerted significant anti-cancer effects in EOC cells and xenograft models including PDX. These results warrant further investigation in clinical trials.
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OBJECTIVE: Endometrial cancer is the most common malignant tumor of the female genital tract. Its incidence has increased in recent years, making up 13% of female genital cancers. Nevertheless, the search for agents effective in the treatment of either advanced or recurrent endometrial cancer has been disappointing. Histone deacetylase inhibitors (HDACIs) were recently found to be well-tolerated in patients with hematologic and solid malignancies. HDACIs have been shown to inhibit cancer cell proliferation, stimulate apoptosis, and induce cell cycle arrest. Our purpose was to investigate the antiproliferative effects of the HDACIs (sodium butyrate and HDAC-I1) against endometrial cancer cell line (Hec 1A) and normal endometrial cell line (T-HESCs). METHODS: MTS reduction assay was carried out to determine the cell viability. Cell cycle analysis and DNA fragmentation assay was done by fluorescent activated cell sorter analysis. The expression of cell cycle-regulatory and apoptosis-related proteins were evaluated by Western blot. Caspase 3 and 7 activity were measured by immuno-flouorescent staining. RESULTS: Each sodium butyrate and HDAC-I1 induced growth inhibition in a dose and time dependent manner in endometrial cancer cells but did not induce growth inhibition in normal endometrial cells. Treatment with each drugs in endometrial cancer cells increased the percentage of cells in subG1 phase. The expression of p53, p21, p27, FAS, and FAS legand were increased and it was associated with increased p21 and p27 expression in a p53-dependent manner. Activation of caspase-3, 7, 8, 9 and down-regulation of Bcl-2, up-regulation of Bax, with concomitant increase in PARP cleavage, were observed. CONCLUSION: These results demonstrate that sodium butyrate induced growth inhibition and apoptosis in human endometrial cancer cells rising their possibility applicable against human endometrial cancers.