Apoptosis-inducing Costunolide and a novel acyclic monoterpene from the stem bark ofMagnolia sieboldii

Abstract

In a course of obtaining more amount of bioactive costunolide and successive phytochemical isolation from Magnolia sieboldii (Magnoliaceae), a novel acyclic monoterpene 1 named deoxygeraniol [2,6(E)-dimethyl-2,6-octadiene] was isolated along with beta-sitosterol 3-O-linoleate (2), trilinolein (3) and high amount of costunolide (4) in the pure state. The structure of compound 1 was determined on the basis of spectroscopic data. Costunolide was found to induce apoptotic cell death in a dose-dependent manner by nucleosomal DNA ladder and flow cytometric analysis. Immunoblot analysis showed that the level of the anti-apoptotic protein, Bcl-2, was decreased, whereas the cleavage of poly-(ADP-ribose) polymerase was activated. Furthermore, the N-acetyl-L-cysteine antioxidant effectively prevented costunolide-induced cytotoxicity. These results suggest that costunolide-induced cell death is mediated by reactive oxygen species

Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

“…Furthermore, the N-acetyl-L-cysteine antioxidant effectively prevented costunolide-induced cytotoxicity. These results suggested that costunolide-induced cell death is mediated by reactive oxygen species (Park HJ et al, 2001). Other results indicate that costunolide-induced c-Jun N-terminal kinase (JNK) activation acts downstream of ROS but upstream of Bcl-2, and suggest that ROS-mediated JNK activation plays a key role in costunolide-induced apoptosis.…”

Costunolide Triggers Apoptosis in Human Leukemia U937 Cells by Depleting Intracellular Thiols

“…Costunolide used for this study was isolated from the stem bark of Magnolia sieboldii as previously described. 12,13) Cell culture and costunolide treatment Human promonocytic leukemia U937 cells were obtained from the Japanese Cancer Research Resources Bank (Tokyo) and Bcl-2-overexpressing U937 bcl-2H were constructed as previously described.…”

“…12,13) As intracellular thiols play an important role in maintaining cellular redox equilibrium that is pivotal for cell survival, we hypothesized that costunolide may change intracellular redox status and thus trigger apoptosis. In this study, the molecular mechanisms of apoptosis induced by costunolide and the role of Bcl-2 were investigated in human promonocytic leukemia U-937 cells.…”

Costunolide: A novel anti-cancer sesquiterpene lactone

“…It has been reported that some kinds of sesquiterpene compounds induced apoptosis in cancer cells (Furuya et al, 1994;Woynarowski et al, 1997) and costunolide was also proven to have preventive effects on intestinal carcinogenesis, (Mori et al, 1994) suggesting an apoptosis-inducing activity of costunolide. Studies demonstrate that costunolide induces apoptosis in HL-60 human leukemia cells by the ROS-mediated mitochondrial permeability transition and resultant cytochrome c release , activates the cleavage of poly-(ADP-ribose) polymerase (Park et al, 2001a), by depleting intracellular thiols (Choi et al, 2002a) and inducing the chromatin condensation (Hibasami et al, 2003;Komiya et al, 2004). Costunolide -induced apoptotic mechanisms are that the receptormediated pathway precedes the mitochondriadependent pathway, caused by the inhibition of telomerase activity via suppression of hTERT in NALM-6 cells (Kanno et al, 2008), alters the balance of antiapoptotic Bcl-2 (Choi et al, 2002a;Rasul et al, 2011) and induces apoptosis by activation of c-Jun N-terminal kinase (JNK) in leukemic U937 cells (Choi and Lee, 2009) and inhibition of the prosurvival Akt and nuclear factor kappa B signaling pathway in human endometriotic epithelial cells (Kim et al, 2011a).…”

“…Accumulated data indicate that Costunolide was isolated from many plant species such as Saussurea lappa Li et al, 2006;Zhang et al, 2011), Aucklandia lappa Decne (Li et al, 2005;Rasul et al, 2011), Michelia floribunda (Mondranondra et al, 1990), Magnolia grandiflora (el-Feraly and Chan, 1978;, Podachaenium eminens (Castro et al, 2000), Magnolia sieboldii (Park et al, 2001a;Park et al, 2001b), Tsoongiodendron odorum Chun (Song et al, 2001), Cosmos pringlei (Mata et al, 2002), Laurus nobilis (De Marino et al, 2005;Matsuda et al, 2002), Laurus novocanariensis (Ferrari et al, 2005), Magnolia kobus (Park et al, 2010), Eupatorium lindleyanum , and Magnolia ovata (Kassuya et al, 2009).…”