morin and Prostatic-Neoplasms

Paclitaxel is a first-line microtubule-stabilizing drug in treating prostate cancer. However, most patients develop resistance and experience relapse. Morin (3,5,7,20,40-pentahydroxyflavone) is an anti-tumor flavonoid in a numerous types of cancer cells including breast, ovarian and lung cancers. We therefore researched the effects of morin as an adjuvant to paclitaxel in in treating DU145 and PC-3 cells in vitro and DU145 derived prostate cancers in nude mice models. The chemosensitivities of these cells to the treatments of morin and paclitaxel were tested through viability assays utilizing cell counting kit 8 (CCK-8) and apoptosis assays through flow cytometry analyses. MicroRNA (miRNA) microarray was employed to determine the changes in miRNA profile of morin treated DU145 cells. The results from microarrays were further certified by quantitative real-time reverse transcription-PCR (qRT-PCR). The underlying targets of miR-155 were verified using luciferase assays followed by Western blot assays. In the results, morin was capable of repressing the cell viabilities in the paclitaxel-treated cells. MiR-155might be an effective target that can be down-regulated in morin-treated cells. We also discovered that GATA binding protein 3 (GATA3) was directly repressed by miR-155, and the treatment of morin reversed the expression of GATA3. In conclusion, morin might be a potential adjuvant of paclitaxel in treating prostate cancer through regulating miR-155/GATA3 axis.

Topics: 3' Untranslated Regions; Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Cluster Analysis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Flavonoids; GATA3 Transcription Factor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Male; Mice; MicroRNAs; Paclitaxel; Prostatic Neoplasms; RNA Interference; Xenograft Model Antitumor Assays

The pim-1 kinase is a true oncogene that has been implicated in the development of leukemias, lymphomas, and prostate cancer, and is the target of drug development programs. We have used experimental approaches to identify a selective, cell-permeable, small-molecule inhibitor of the pim-1 kinase to foster basic and translational studies of the enzyme. We used an ELISA-based kinase assay to screen a diversity library of potential kinase inhibitors. The flavonol quercetagetin (3,3',4',5,6,7-hydroxyflavone) was identified as a moderately potent, ATP-competitive inhibitor (IC(50), 0.34 micromol/L). Resolution of the crystal structure of PIM1 in complex with quercetagetin or two other flavonoids revealed a spectrum of binding poses and hydrogen-bonding patterns in spite of strong similarity of the ligands. Quercetagetin was a highly selective inhibitor of PIM1 compared with PIM2 and seven other serine-threonine kinases. Quercetagetin was able to inhibit PIM1 activity in intact RWPE2 prostate cancer cells in a dose-dependent manner (ED(50), 5.5 micromol/L). RWPE2 cells treated with quercetagetin showed pronounced growth inhibition at inhibitor concentrations that blocked PIM1 kinase activity. Furthermore, the ability of quercetagetin to inhibit the growth of other prostate epithelial cell lines varied in proportion to their levels of PIM1 protein. Quercetagetin can function as a moderately potent and selective, cell-permeable inhibitor of the pim-1 kinase, and may be useful for proof-of-concept studies to support the development of clinically useful PIM1 inhibitors.

Topics: Chromones; Crystallography, X-Ray; Flavones; Flavonoids; Humans; Male; Phenotype; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein Structure, Secondary; Proto-Oncogene Proteins c-pim-1; Sensitivity and Specificity; Substrate Specificity