kaempferol and Prostatic-Neoplasms

A library of flavonol analogues was synthesised and evaluated as potential anticancer agents against a human prostate cancer cell line, 22rν1. Compounds 3, 8 and 11 (IC(50) 2.6, 3.3 and 4.0 μM respectively) showed potent cancer cell growth inhibition, comparable to the lead compound 3',4',5'-trimethoxyflavonol (1) (IC(50) 3.1 μM) and superior to the naturally occurring flavonols quercetin (16) and fisetin (22) (both >15 μM). Results indicate that the 3',4',5'- arrangement of either hydroxy (OH) or methoxy (OMe) residues is important for growth arrest of these cells and that the OMe analogues may be superior to their OH counterparts. Compounds 1, 3, 8 and 11 warrant further investigation as potential agents for the management of prostate cancer.

Topics: Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Chemistry Techniques, Synthetic; Drug Stability; Flavonols; Humans; Hydrophobic and Hydrophilic Interactions; Male; Prostatic Neoplasms

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