agar and Endometrial-Neoplasms

HDAC inhibitors (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 [suberoyl anilide bishydroxamine, valproic acid (VPA), trichostatin A, and sodium butyrate] against six endometrial cancer cell lines.. Endometrial cancer cells were treated with a variety of HDACIs, and the effect on cell growth, cell cycle, and apoptosis was measured. The ability of VPA to inhibit the growth of endometrial tumors growing in immunodeficient mice was also assessed.. Clonogenic assays showed that all cancer cell lines were sensitive to the growth inhibitory effect of HDACIs. Cell cycle analysis indicated that treatment with HDACIs decreased the proportion of cells in S phase and increased the proportion of cells in the G(0)-G(1) and/or G(2)-M phases of the cell cycle. Terminal deoxynucleotidyl transferase-mediated nick end labeling assays showed that HDACIs induced apoptosis. This was concomitant with altered expression of genes related to malignant phenotype, including an increase in p21(Waf1), p27(Kip7), and E-cadherin and a decrease in Bcl-2 and cyclin-D1 and -D2. Chromatin immunoprecipitation analysis revealed a remarkable increase in levels of acetylated histones associated with the p21 promoter after suberoyl anilide bishydroxamine treatment. In nude mice experiments, VPA inhibited significantly human uterine tumor growth without toxic side effects.. These results suggest that HDACIs are effective in inhibiting growth of endometrial cancer cells in vitro and in nude mice, without toxic side effects. The findings raise the possibility that HDACIs may prove particularly effective in treatment of endometrial cancers.

Topics: Agar; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Cadherins; Cell Cycle Proteins; Cell Division; Cell Line, Tumor; Chromatin; Cyclin D1; Cyclin D2; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Dose-Response Relationship, Drug; Endometrial Neoplasms; Enzyme Inhibitors; Female; Flow Cytometry; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; In Situ Nick-End Labeling; Mice; Mice, Nude; Precipitin Tests; Proto-Oncogene Proteins c-bcl-2; S Phase; Sodium Oxybate; Time Factors; Tumor Suppressor Proteins; Valproic Acid; Vorinostat

Morphofunctional peculiarities of tumor cells from 15 endometrial adenocarcinomas and 2 ovarian tumors have been investigated at the ultrastructural level. These cells could develop two types of colonies in soft agar: those with histotypical differentiation (numerous microvilli, well developed tight junctions, desmosomes, secretory granules), and those without it (absence of epithelial features, ability of tumor cells to produce filamentous extracellular matrix and striated collagen fibrils which are characteristic of fibroblastic cells). The addition of progesterone and tamoxifen to cell cultures resulted in rising the level of cell differentiation in the colonies. The fact that endometrial and ovarian cancer cells can express the properties specific of connective tissue cells may suggest a multipotention of the Mullerian epithelium derivatives to shed light on the histogenesis of the mixed Mullerian tumors of uterus.

Topics: Adenocarcinoma; Agar; Cell Transformation, Neoplastic; Culture Media; Cystadenocarcinoma; Endometrial Neoplasms; Female; Granulosa Cell Tumor; Humans; Methotrexate; Microscopy, Electron; Morphogenesis; Ovarian Neoplasms; Progesterone; Tamoxifen; Tumor Cells, Cultured