Apoptosis induction of human leukemia U937 cells by gomisin N, a dibenzocyclooctadiene lignan, isolated from Schizandra chinensis Baill.
We compared the pro-apoptotic effect of two dibenzocyclooctadiene lignans, gomisin A and gomisin N, isolated from Schizandra chinensis Baill, in U937 human promyelocytic leukemia cells in vitro. Gomisin N, but not gomisin A, inhibited cell growth in a dose-dependent manner, which was associated with the induction of apoptosis. The increase in apoptosis that was induced by gomisin N was correlated with down-regulation of anti-apoptotic Bcl-2 expression, a decrease in the mitochondrial membrane potential (MMP) and a release of cytochrome c from the mitochondria into the cytosol. Furthermore, gomisin N induced the proteolytic activation of caspase-9 and -3 and a concomitant degradation of poly(ADP-ribose) polymerase. However, caspase-8 was not activated and cleavage of Bid was not observed in gomisin N-treated U937 cells. The cytotoxic effects and apoptotic characteristics induced by gomisin N were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, demonstrating the important role that caspase-3 plays in the process. We conclude that gomisin N induces the apoptosis of U937 cells through a signaling cascade of mitochondria-mediated intrinsic caspase pathways and gomisin N may be a useful chemotherapeutic agent.
Kim
Jong-Hwan
JH
Department of Oriental Medicine, Dongeui University College of Oriental Medicine, Busan 614-052, Republic of Korea.
Choi
Young-Whan
YW
Park
Cheol
C
Jin
Cheng-Yun
CY
Lee
You Jin
YJ
Park
Da Jung
DJ
Kim
Sun Guen
SG
Kim
Gi-Young
GY
Choi
Il-Whan
IW
Hwang
Won-Deuk
WD
Jeong
Yong Kee
YK
Kim
Se-Kwon
SK
Choi
Yung Hyun
YH
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D034242:Cyclooctanes / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D004149:Dioxoles / Q000494:pharmacology; D005434:Flow Cytometry; D005638:Fruit / Q000737:chemistry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011083:Polycyclic Compounds / Q000494:pharmacology*; D032141:Schisandra / Q000737:chemistry*; D020298:U937 Cells
D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D034242:Cyclooctanes; D004149:Dioxoles; D017705:Lignans; D011083:Polycyclic Compounds; C015499:schizandrin B; D019938:Cyclin D1; C033585:schizandrol B; D045304:Cytochromes c; D053148:Caspase 3