3-Hydroxyflavone inhibits endogenous Aurora B and induces growth inhibition of cancer cell line.

Abstract

The Aurora kinases play a critical role in mitosis and have been suggested as promising targets for cancer therapy due to their frequent overexpression in a variety of tumors. Compared with established inhibitors of cell division such as the anti-tubulins, novel agents target mitotic enzymes and show similar efficacy but with fewer side effects. Several small-molecule inhibitors of Aurora kinases have been developed as anticancer agents, some of which have progressed to early clinical evaluation. Here we identified 3-hydroxyflavone as a novel Aurora B inhibitor through high throughput screening. 3-Hydroxyflavone showed potent inhibition to Aurora B with the IC(50) on a nanomolar basis in the enzyme-based kinase activity assay. In the cell-based western blotting analysis, 3-hydroxyflavone dramatically decreased the phosphorylation level of Histone H3 on the site of serine 10, demonstrating the potent endogenous Aurora B activity inhibition in cell level. The followed cell image analysis provided the consist result. To make it clear whether 3-hydroxyflavone inhibited Aurora B by direct binding or not, SPR analysis was carried out to measure the affinity of interaction between Aurora B protein and 3-hydroxyflavone and the result proved the binding with high affinity. Usually Aurora activity suppression induced cancer cell proliferation inhibition. Colony formation and cell viability with/without treatment of 3-hydroxyflavone were measured using CCK-8. The growth suppression under 3-hydroxyflavone present and the growth recovery after being released gave strong evidence that presence of 3-hydroxyflavone efficiently inhibited the fast growth of cancer cells.

• Authors: Qingyu Lang, Haoxing Zhang, Jie Li, Fang Xie, Yifeng Zhang, Bo Wan, Long Yu
• Journal: Molecular biology reports (Mol Biol Rep) Vol. 37 Issue 3 Pg. 1577-83 (Mar 2010) ISSN: 1573-4978 [Electronic] Netherlands
• PMID: 19437133 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Flavonoids
• Histones
• AURKB protein, human
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases
• 3-hydroxyflavone

Topics

• Antineoplastic Agents (pharmacology)
• Aurora Kinase B
• Aurora Kinases
• Blotting, Western
• Cell Proliferation (drug effects)
• Flavonoids (chemistry, pharmacology)
• HeLa Cells
• Histones (metabolism)
• Humans
• Inhibitory Concentration 50
• Molecular Structure
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Surface Plasmon Resonance
• Tumor Stem Cell Assay