Inhibition of the G2 DNA Damage Checkpoint and of Protein Kinases Chk1 and Chk2 by the Marine Sponge Alkaloid Debromohymenialdisine

摘要: Abstract Cells can respond to DNA damage by activating checkpoints that delay cell cycle progression and allow time for repair. Chemical inhibitors of the G2 phase checkpoint may be used as tools understand better how is regulated sensitize cancer cells DNA-damaging therapies. However, few are known. We a cell-based assay screen natural extracts G2checkpoint identified debromohymenialdisine (DBH) from marine sponge. DBH distinct structurally previously known inhibitors. It inhibited with an IC50 8 μm showed moderate cytotoxicity (IC50 = 25 μm) toward MCF-7 cells. kinases Chk1 3 Chk2 3.5 but not ataxia-telangiectasia mutated (ATM), ATM-Rad3-related protein, or DNA-dependent protein kinase in vitro, indicating it blocks two major branches pathway downstream ATM. did cause activation inhibition different signal transduction proteins, determined mobility shift analysis Western blots, suggesting inhibits narrow range vivo.