stilbenes and Uterine-Neoplasms

Leiomyomas (myomas) are the most common benign smooth muscle cell tumor of the myometrium. Resveratrol, a stilbene, has been used as an anti-inflammatory and antitumor agent. In the current study, we investigated the inhibitory effect of resveratrol on the proliferation of primary human myoma cell cultures. Resveratrol arrested cell proliferation via integrin αvβ3. It also inhibited integrin αvβ3 expression and protein accumulation. Concurrently, constitutive AKT phosphorylation in myoma cells was inhibited by resveratrol. Expressions of proapoptotic genes, such as cyclooxygenase (COX)-2, p21 and CDKN2, were induced by resveratrol in myoma cells. On the other hand, expressions of proliferative (anti-apoptotic) genes were either inhibited, as in BCL2, or unchanged, as in cyclin D1 and proliferating cell nuclear antigen (PCNA). The accumulation of insulin-like growth factor (IGF)-1 receptor (IGF-1R) was inhibited by resveratrol in primary myoma cells. IGF-1-induced cell proliferation was inhibited by co-incubation with resveratrol. Therefore, growth modulation of myoma cells occurs via mechanisms dependent on cross-talk between integrin αvβ3 and IGF-1R. Our findings suggest that resveratrol can be considered an alternative therapeutic agent for myomas.

Topics: Cell Proliferation; Female; Flow Cytometry; Humans; In Situ Nick-End Labeling; Integrin alphaVbeta3; Leiomyoma; Phosphorylation; Receptor Cross-Talk; Receptor, IGF Type 1; Resveratrol; Stilbenes; Uterine Neoplasms

Lymphangioleiomyomatosis (LAM) is a rare neoplastic metastatic disease affecting women of childbearing age. LAM is caused by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) as a consequence of tuberous sclerosis complex (TSC) 1/2 inactivation. Clinically, LAM results in cystic lung destruction. mTORC1 inhibition using rapamycin analogs (rapalogs) is partially effective in reducing disease progression and improving lung function. However, cessation of treatment results in continued progression of the disease. In the present study, we investigated the effectiveness of the combination of rapamycin treatment with resveratrol, an autophagy inhibitor, in the TSC2-null xenograft tumor model. We determined that this combination inhibits phosphatidylinositol-4,5-bisphosphate 3-kinase PI3K/Akt/mTORC1 signaling and activates apoptosis. Therefore, the combination of rapamycin and resveratrol may be an effective clinical strategy for treatment of LAM and other diseases with mTORC1 hyperactivation.

Topics: Animals; Antineoplastic Agents; Apoptosis; Drug Therapy, Combination; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphangioleiomyomatosis; Mechanistic Target of Rapamycin Complex 1; Mice, SCID; Multiprotein Complexes; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Resveratrol; Signal Transduction; Sirolimus; Stilbenes; TOR Serine-Threonine Kinases; Treatment Outcome; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Uterine Neoplasms; Xenograft Model Antitumor Assays

The purpose of this study was to investigate whether resveratrol adds to the growth inhibitory effects of cisplatin and doxorubicin on ovarian and uterine cancer cells and to evaluate whether resveratrol diminishes the cardiac toxicity of doxorubicin in rodent heart.. Human ovarian (OVCAR-3) and uterine (Ishikawa) cancer cells in culture were treated with cisplatin and doxorubicin, respectively, with and without resveratrol; and cell growth and viability were evaluated. Neonatal rat ventricular myocytes received doxorubicin in the presence and absence of resveratrol, and cell viability was evaluated. Mice received doxorubicin +/- resveratrol, and electrocardiograms were evaluated. Data were analyzed with analysis of variance and Scheffe's test.. Resveratrol combined with cisplatin or with doxorubicin demonstrated an additive growth-inhibitory anticancer effect with a left shift of the cisplatin and doxorubicin dose/response curves. Resveratrol increased the viability of neonatal rat ventricular myocytes that were treated with doxorubicin and reduced doxorubicin-induced bradycardia and QTc interval prolongation in mice.. Resveratrol adds to the growth inhibitory/anticancer activity of cisplatin and doxorubicin in vitro and protects against doxorubicin-induced cardiac toxicity both in vitro and in mice.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bradycardia; Cardiotonic Agents; Cell Division; Cell Survival; Cells, Cultured; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Female; Humans; Long QT Syndrome; Mice; Myocytes, Cardiac; Ovarian Neoplasms; Rats; Resveratrol; Stilbenes; Uterine Neoplasms

Endometrial cancer is the fourth most prominent cancer among all feminine cancers in the Western world. Resveratrol, a natural anti-oxidant found in red wine emerging as a novel anticancer agent, exerts antiproliferative and pro-apoptotic activity in various cancer cell types, but its effect on uterine cancer cells is poorly understood. At the molecular level, resveratrol has been reported to inhibit cyclooxygenase (COX) expression and/or activity; in endometrial cancer cells, COX-2 is overexpressed and confers cellular resistance to apoptosis. The aim of the present study was to determine if resveratrol could exert anti-proliferative and pro-apoptotic activity over uterine cancer cells upon inhibition of COX-2 expression and/or activity. Six different human uterine cancer cell lines were used as a model (HeLa, Hec-1A, KLE, RL95-2, Ishikawa and EN-1078D).. High-dose of resveratrol triggered apoptosis in five out of six uterine cancer cell lines, as judged from Hoechst nuclear staining and effector caspase cleavage. In accordance, uterine cancer cell proliferation was decreased. Resveratrol also reduced cellular levels of the phosphorylated/active form of anti-apoptotic kinase AKT. Endogenous COX-2 protein levels were decreased, concomitant with a decrease in production of COX metabolites PGE2 and PGF2alpha, in each uterine cancer cell line expressing detectable levels of COX-1 and/or COX-2 in presence of resveratrol. Although COX expression was identified as a target of resveratrol in uterine cancer cells, inhibition of COX activity or exogenously added PGE2 did not modulate the effect of resveratrol on cellular proliferation.. High-dose of resveratrol exerts tumoricidal activity over uterine cancer cells and regulates COX expression. In these cells, resveratrol would not directly target COX activity, but possibly other enzymes involved in prostaglandin synthesis that act downstream of the COXs.

Topics: Apoptosis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Endometrial Neoplasms; Female; HeLa Cells; Humans; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes; Uterine Neoplasms

Scutellaria barbata D. Don (SB) is one of the herbs belonging to perennial plants, which is known in traditional Korean medicine as 'Ban-Ji-Ryun,' and has been used as an anti-inflammatory and anti-tumor agents against human uterine leiomyoma, mammalian and ovarian cancers. Although the difference between uterine smooth muscle cell (SMC) and leiomyomal SMCs has not been clearly established, the action of SB water extract was investigated using SMCs from normal myometrium and leiomyoma. The proliferation of cultured myometrial and leiomyomal SMC was inhibited by SB treatment. Flow cytometric analysis showed that the population in the G1 phase of the cell cycle increased under SB treatment. Western blotting analysis showed that markers of SMC differentiation such as alpha-smooth muscle actin (alpha-SMA), calponin h1 and cyclin-dependent kinase inhibitor p27 were induced by treatment with SB in myometrial and leiomyomal SMCs. In contrast, cell-cycle-related gene products from the G1 phase of the cell cycle, such as cyclin E and cdk2, were not affected. Taken together, these results indicate that SB inhibits the proliferation of myometrial and leiomyomals SMC through the induction of alpha-SMA, calponin h1 and p27. It is suggested that SB may induce differentiation in uterine SMC and may influence tissue remodeling and reconstruction during physiological and pathophysiological events.

Topics: Antineoplastic Agents; Berberine; Blotting, Western; Cell Cycle; Cell Proliferation; Cells, Cultured; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Flavonoids; Flow Cytometry; Humans; Leiomyoma; Myocytes, Smooth Muscle; Myometrium; Plant Extracts; Plant Stems; Resveratrol; Scutellaria; Stilbenes; Tumor Cells, Cultured; Uterine Neoplasms

Nonsteroidal anti-oestrogenic drugs, tamoxifen and clomiphene citrate, at concentrations higher than 0.001 mug/ml reduced the colony forming ability of cells derived from a rat uterine adenocarcinoma in vitro. The 50 per cent inhibitory dose of these drugs was about one-hundredth of that of sex steroids. When the cells were treated with combinations of these nonsteroidal anti-oestrogenic drugs and the 50 per cent inhibitory dose (8 mug/ml) of progesterone, a synergistic effect on the inhibition of colony formation was observed. In contrast to progesterone, oestradiol-17beta (the 50 per cent inhibitory dose of which was about 16 mug/ml) suppressed additively the colony formation only in combination with low doses of anti-oestrogenic drugs.

Topics: Adenocarcinoma; Animals; Cell Division; Clomiphene; Estradiol; Female; Progesterone; Rats; Stilbenes; Tamoxifen; Uterine Neoplasms; Uterus

Topics: Adenocarcinoma; Breast Neoplasms; Centrifugation, Density Gradient; Cytosol; Estradiol; Female; Humans; Protein Binding; Receptors, Cell Surface; Stilbenes; Tamoxifen; Uterine Neoplasms

Topics: 17-Ketosteroids; Adenocarcinoma; Atrophy; Chorionic Gonadotropin; Clomiphene; Diagnosis; Drug Therapy; Endometriosis; Endometrium; Female; Follicle Stimulating Hormone; Genital Diseases, Female; Gonadotropins; Humans; Hyperplasia; Infertility; Infertility, Female; Ovulation; Pathology; Polycystic Ovary Syndrome; Stilbenes; Toxicology; Urine; Uterine Neoplasms

Topics: Carcinoma; Endometrial Hyperplasia; Endometrium; Female; Humans; Menopause; Stilbenes; Uterine Neoplasms

Topics: Carcinoma; Carcinoma, Squamous Cell; Clomiphene; Endometrial Hyperplasia; Female; Hemorrhage; Humans; Metrorrhagia; Pathology; Stilbenes; Uterine Neoplasms

Topics: Animals; Antimetabolites; Deciduoma; Estradiol; Estrogens; Female; Humans; Hydatidiform Mole, Invasive; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Pregnancy; Pregnancy, Animal; Research; Stilbenes; Uterine Neoplasms