Antagonistic effect of flavonoids on NSC-741909-mediated antitumor activity via scavenging of reactive oxygen species

NSC-741909 (1 [(4-chlorophenyl)methyl] 1H Indole-3-methanol) is a novel anticancer agent that is highly active against several NCI-60 cancer cell lines This agent induces sustained activation of mitogen activated protein kinases (MAPK) including JNK and p38 MAP kinases However the mechanisms of its selective antitumor activity in some cancer cell lines remain unknown We tested the combined effects of NSC 741909 and several kinase inhibitors that target the Raf/MEK/ERK1/2 or PI3K/AKT pathways in two sensitive lung cancer cells We found that PD98059 (2'-amino-3' methoxyflavone) a flavone derivative and a selective MEK inhibitor can dramatically block the cell killing effect of NSC-741909 To determine whether this inhibitory effect is associated with MEK inhibition or other mechanisms we evaluated the effects of other MEK inhibitors with different chemical structures and flavone derivatives that do not have an effect on MEK We found that several flavonoids can markedly block NSC 741909-induced apoptosis and JNK activation in a time-dependent manner regardless of whether they inhibit MEK or not In contrast NSC-741909-induced JNK activation and apoptosis were not blocked by other MEK-specific inhibitors U0126 and CI1040 Our results also showed that NSC 741909 induced a dramatic Increase of reactive oxygen species in sensitive cells and that flavonoids effectively blocked the NSC 741909-induced reactive oxygen species production which are associated with flavonoids antagonistic effects on NSC-741909 induced JNK activation and apoptosis Those results demonstrated that flavonoids mediated antagonist effect is through scavenging of reactive oxygen species Our results may have implication on the design of clinical evaluation of antitumor activity of NSC 741909 or its analogues (C) 2010 Elsevier B V All rights reserved