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.