TY - JOUR
T1 - Antagonistic effect of flavonoids on NSC-741909-mediated antitumor activity via scavenging of reactive oxygen species
AU - Guo, Wei
AU - Wei, Xiaoli
AU - Wu, Shuhong
AU - Wang, Li
AU - Peng, Henry
AU - Wang, Ji
AU - Fang, Bingliang
N1 - Funding Information:
We would like to thank Alyson Todd for her editorial review of this manuscript. This work was supported by National Cancer Institute grants R01 CA 092487 and RO1 CA 124951 (B. Fang) and Cancer Center Support Grant ( CA 16672 ), National Natural Science Foundation of China No. 30973563 (to X. Wei), Zhejiang Science Foundation ( 2008C14080 ) and INNOFUND of China ( 09C26213301228 ).
PY - 2010/12/15
Y1 - 2010/12/15
N2 - NSC-741909 (1-[(4-chlorophenyl)methyl]-1. H-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.
AB - NSC-741909 (1-[(4-chlorophenyl)methyl]-1. H-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.
KW - Antitumor
KW - Flavonoids
KW - JNK
KW - NSC-741909
KW - Reactive oxygen species
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U2 - 10.1016/j.ejphar.2010.08.057
DO - 10.1016/j.ejphar.2010.08.057
M3 - Article
C2 - 20854805
AN - SCOPUS:78049261467
SN - 0014-2999
VL - 649
SP - 51
EP - 58
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -