cyclin-d1 and deguelin

The overexpression of cyclin D1 and cyclin E due to their oncogenic potential and amplification has been associated with a higher mortality rate in many cancers. The deguelin is a natural compound, has shown promising anti-cancer activity by directly binding cyclin D1 and cyclin E and thus suppressing its function. The C7a atomic position of deguelin structure contains a proton that generates stabilized radical, as a result, decomposed deguelin reduces its structural stability and significantly decreases its biological activity. To design deguelin derivatives with the reduced potential side effect, series of B, C-ring truncated derivatives were investigated as cyclin D1 and cyclin E inhibitors. R-group-based enumeration was implemented in the deguelin scaffold using the R-group enumeration module of Schrödinger. Drug-Like filters like, REOS and PAINs series were applied to the enumerated compound library to remove compounds containing reactive functional groups. Further, screened compounds were docked within the ligand-binding cavity of cyclin D1 and cyclin E crystal structure, using Glide SP and XP protocol to obtain docking poses. Enrichment calculations were done using SchrÖdinger software, with 1000 decoy compounds (from DUD.E database) and 60 compounds (XP best poses) along with deguelin, to validate the docking protocol. The receiver operating characteristic (ROC) curve indicates R

Topics: Cyclin D1; Cyclin E; Molecular Docking Simulation; Molecular Dynamics Simulation; Rotenone

Deguelin is a major active ingredient and principal component in several plants and it is a potential molecule to target proteins of cancer cell signaling pathway. As a complex natural extract, deguelin interacts with various molecular targets to exert its anti-tumor properties at nanomolar level. It induces cell apoptosis by blocking anti-apoptotic pathways, while inhibiting tumor cell multiplication and malignant transformation through p27-cyclin-E-pRb-E2F1- cell cycle control and HIF-1alphaVEGF antiangiogenic pathways. In silico studies of deguelin and its derivatives is performed to explore interactions with Cyclin D1 and Cyclin E to understand the molecular insights of derivatives with the receptors. Deguelin and its derivatives are minimized by Avogadro to achieve stable conformation. All docking simulation are performed with AutoDockVina and virtual screening of docked ligands are carried out based on binding energy and number of hydrogen bonds. Molecular dynamics (MD) and Simulation of Cyclin D1 and Cyclin E1 is performed for 100 ns and stable conformation is obtained at 78 ns and 19 ns respectively. Ligands thus obtained from docking studies may be probable target to inhibit cancer cell signaling pathways.

Topics: Amino Acid Sequence; Computational Biology; Cyclin D1; Cyclin E; Humans; Hydrogen Bonding; Molecular Docking Simulation; Protein Binding; Rotenone; Sequence Homology, Amino Acid; Signal Transduction

To investigate the anticancer effects and molecular mechanism of deguelin on human Burkitt's lymphoma Daudi cells in vitro and compare the cytotoxicity of deguelin on Daudi cells and human peripheral blood monocular cells (HPBMC).. The effects of deguelin on the growth of Daudi cells were studied by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5 diphenyl-2H-tetrazolium (MTT) assay. Apoptosis was assessed through Hoechst 33258 staining and annexin V/PI double-labeled cytometry. The effect of deguelin on the cell cycle of Daudi cells was studied by propidium iodide method. The expressions of cyclin D1 and pRb were checked by Western blot.. The proliferation of Daudi cells was decreased in deguelin-treated group with a 24 h IC50 value of 51. 55 nmol/L. Deguelin induced Daudi cells apoptosis in a time- and dose-dependent manner. Daudi cells treated with deguelin showed an increase of G0/G1 phase and decrease of S phase. The Daudi cells treated with 0, 5, 10, 20, 40 nmol/L deguelin for 24 h, showed an increased Go/G, phase from 37.34% to 56.56% , whereas decreased S phase from 37.72% to 21.36%, respectively. PBMC was less sensitive to the cytotoxic effect of deguelin than Daudi cells. The expression of cyclin D1 and pRb protein were decreased in Daudi cells treated with deguelin.. Deguelin can inhibit the proliferation of Daudi cells by regulating the cell cycle that arrest cells at G0/G1 phase and inducing apoptosis. Moreover, deguelin demonstrats low toxicity in PBMC but selectively induces apoptosis of Daudi cells. The antitumor effects of deguelin may be related to down-regulation of the expression of cyclin D1 and pRb protein.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Burkitt Lymphoma; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Dose-Response Relationship, Drug; Down-Regulation; Flow Cytometry; Humans; Leukocytes, Mononuclear; Retinoblastoma Protein; Rotenone

To investigate anticancer effects and molecular mechanism of deguelin on human Burkittos lymphoma Daudi cells in vitro and compare the cytotoxicities of deguelin on Daudi cells and human peripheral blood monocular cells (PBMC).. The effects of deguelin on the growth of Daudi cells were studied by 3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) assay. Apoptosis were detected through Hoechst 33258 staining and Annexin V/PI double-labeled cytometry. The effect of deguelin on the cell cycle of Daudi cells were studied by a propidium iodide method. The expressions of cyclin D1 and pRb were checked by Western blot.. The proliferation of Daudi cells were decreased in deguelin-treated group with a 24-h IC50 value of 51.55 nmol/L. Deguelin induced Daudi cells apoptosis was in a time- and dose-dependent manner. G0/G1 phase increased and S phase decreased in Daudi cells treated with deguelin. With deguelin 0, 5, 10, 20, and 40 nmol/L treatment for 24 h, G0/G1 phase increased from 37.34% to 56.56%, whereas S phase decreased from 37.72% to 21.36%. PBMC was less sensitive to the cytotoxic effect of deguelin than Daudi cells. The expression of cyclin D1 and pRb protein were decreased sharply in Daudi cells treated with deguelin.. Deguelin is able to inhibit the proliferation of Daudi cells by regulating the cell cycle that arrested cells at G0/G1 phase and inducing the cell apoptosis. Moreover, deguelin selectively induced apoptosis of Daudi cells with low toxicity in PBMC. The antitumor effects of deguelin were related to down-regulating the expression of cyclin D1 and pRb protein.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Burkitt Lymphoma; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Dose-Response Relationship, Drug; Humans; Leukocytes, Mononuclear; Retinoblastoma Protein; Rotenone