Costunolide triggers apoptosis in human leukemia U937 cells by depleting intracellular thiols.
We have previously demonstrated that costunolide, a biologically active compound that was isolated from the stem bark of Magnolia sieboldii, induced apoptosis in human cancer cells. In the present study, we investigated the underlying mechanisms and suggest that costunolide induces apoptosis in human promonocytic leukemia U937 cells by depleting the intracellular thiols. Costunolide treatment rapidly depleted the intracellular reduced glutathione (GSH) and protein thiols, and this preceded the occurrence of apoptosis. Pretreatment with sulfhydryl compounds such as GSH, N-acetyl-L-cysteine, dithiothreitol and 2-mercaptoethanol almost completely blocked the costunolide-induced apoptosis, highlighting the significance of the intracellular thiol level in the process. Furthermore, overexpression of Bcl-2 also significantly attenuated the effects of costunolide. The apoptosis-inducing activity of costunolide is likely to depend on the exomethylene moiety because derivatives in which this group was reduced, such as dihydrocostunolide and saussurea lactone, did not deplete the cellular thiols and showed no apoptotic activity. Taken together, the present study demonstrates that the costunolide-induced apoptosis depends on intracellular thiols contents, which are modulated by Bcl-2.
Choi
Jung-Hye
JH
College of Pharmacy, Kyung-Hee University, Hoegi-Dong, Dongdaemun-Ku, Seoul 130-701, Korea.
Ha
Joohun
J
Park
Jae-Hoon
JH
Lee
Jae Yeol
JY
Lee
Yong Sup
YS
Park
Hee-Juhn
HJ
Choi
Jong-Won
JW
Masuda
Yutaka
Y
Nakaya
Kazuyasu
K
Lee
Kyung-Tae
KT
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000502:physiology; D012717:Sesquiterpenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000032:analysis*; D020298:U937 Cells; D007783:Lactones
D000972:Antineoplastic Agents, Phytogenic; D005978:Glutathione; D019253:Proto-Oncogene Proteins c-bcl-2; D012717:Sesquiterpenes; D013438:Sulfhydryl Compounds; C002602:costunolide; D007783:Lactones