cyclin-d1 and fascaplysine

Cyclin-dependent kinases (CDKs) are important regulators of the cell cycle; previous studies have shown that misregulation of CDK4 (cyclin-dependent kinase 4) activity can lead to cancer. The present study investigated the anti-tumor effects of a highly selective CDK4 inhibitor fascaplysin in ovarian carcinoma cell lines.. In our study, cell proliferation, cell cycle, cell apoptosis, cell invasion, and cell migration relative assays were performed in ovarian cancer cell lines A2780 and OVCAR3 in the presence of different concentrations of fascaplysin. The protein expression levels of CDK4, cyclin D1, Bcl-2 (B-cell lymphoma-2), and VEGFA (vascular endothelial growth factor A) were determined by western blot.. Our results showed that fascaplysin inhibited ovarian cancer cell proliferation, invasion and migration, as well as inducing S arrest and cell apoptosis. Treatment with fascaplysin also suppressed CDK4, cyclin D1, Bcl-2, and VEGFA expression at protein levels.. Above all, our results showed that fascaplysin has anti-tumor activity against ovarian cancer cell lines through inhibiting CDK4, and may be a therapeutic target for the treatment of ovarian carcinomas.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 4; Female; Gene Expression Regulation, Neoplastic; Humans; Indoles; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian Neoplasms; Proto-Oncogene Proteins c-bcl-2; Vascular Endothelial Growth Factor A

Biphenyl-4-carboxylic acid-[2-(1H-indol-3-yl)-ethyl]-methylamide 1 (CA224) is a nonplanar analogue of fascaplysin (2) that specifically inhibits Cdk4-cyclin D1 in vitro. Compound 1 blocks the growth of cancer cells at G0/G1 phase of the cell cycle. It also blocks the cell cycle at G2/M phase, which is explained by the fact that it inhibits tubulin polymerization. Additionally, it acts as an enhancer of depolymerization for taxol-stabilized tubulin. Western blot analyses of p53-positive cancer cells treated with compound 1 indicated upregulation of p53, p21, and p27 proteins together with downregulation of cyclin B1 and Cdk1. Compound 1 selectively induces apoptosis of SV40 large T-antigen transformed cells and significantly reduces colony formation efficiency, in a dose-dependent manner, of lung cancer cells. It is efficacious at 1/10th of the MTD against human tumors derived from HCT-116 and NCI-H460 cells in SCID mouse models. The promising efficacy of compound 1 in human xenograft models as well as its excellent therapeutic window indicates its potential for clinical development.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Chemistry, Pharmaceutical; Cyclin D1; Cyclin-Dependent Kinase 4; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; Indoles; Inhibitory Concentration 50; Male; Mice; Mice, SCID; Neoplasm Transplantation; Peptides, Cyclic; Tubulin Modulators; Up-Regulation

We present the design, synthesis and biological activity of a new series of substituted 3-(2-(1H-indol-1-yl)ethyl)-1H-indoles and 1,2-di(1H-indol-1-yl)alkanes as selective inhibitors of CDK4/cyclin D1. The compounds were designed to explore the relationship between the connection mode of the indolyl moieties and their CDK inhibitory activities. We found all the above-mentioned designed compounds to be selective inhibitors of CDK4/cyclin D1 compared to the closely related CDK2/cyclin A, with IC(50) for the best compounds 10m and 13a being 39 and 37microm, respectively.

Topics: Binding Sites; Computer Simulation; Cyclin A; Cyclin D1; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Drug Design; Humans; Indoles; Protein Kinase Inhibitors

The design, synthesis and biological activity of a series of non-planar dihydro-beta-carboline and beta-carboline-based derivatives of the toxic anticancer agent fascaplysin is presented. We show these compounds to be selective inhibitors of CDK4 over CDK2 with an IC50 (CDK4-cyclin D1) = 11 micromol for the best compound in the series 4d. The crystallographic analysis of some of the compounds synthesised (3b/d and 4a-d) was carried out, in an effort to estimate the structural similarities between the designed inhibitors and the model compound fascaplysin.

Topics: Carbolines; Crystallography, X-Ray; Cyclin D1; Cyclin-Dependent Kinase 4; Enzyme Inhibitors; Indoles; Inhibitory Concentration 50; Models, Molecular; Molecular Structure