17-Hydroxy-jolkinolide B Inhibits Signal Transducers and Activators of Transcription 3 Signaling by Covalently Cross-Linking Janus Kinases and Induces Apoptosis of Human Cancer Cells

Abstract

Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway occurs frequently in cancer cells and contributes to oncogenesis. Among the members of STAT family, STAT3 plays a pivotal role in the development and progression of human tumors. The STAT3-mediated signaling pathway has been recognized as a promising anticancer target. Here, we show that 17-Hydroxy-jolkinolide B (HJB), a diterpenoid from the Chinese medicinal herb Euphorbia fischeriana Steud, strongly inhibits interleukin (IL)-6-induced as well as constitutive STAT3 activation. Furthermore, we show that HJB directly targets the JAK family kinases, JAK1, JAK2, and TYK2, by inducing dimerization of the JAKs via cross-linking. Addition of DTT or glutathione prevents the JAK crosslinking and blocks the inhibitory effects of HJB on IL-6-induced STAT3 activation, suggesting that HJB may react with cystein residues of JAKs to form covalent bonds that inactivate JAKs. Liquid chromatography/mass spectrometry analysis confirmed that each HJB reacted with two thiols. The effect of HJB on the JAK/STAT3 pathway is specific as HJB has no effect on platelet-derived growth factor, epidermal growth factor, or insulin-like growth factor I signaling pathways. Finally, we show that HJB inhibits growth and induces apoptosis of tumor cells, particularly those tumor cells with constitutively activated STAT3. We propose that the natural compound HJB is a promising anticancer drug candidate as a potent STAT3 signaling inhibitor. [Cancer Res 2009;69(18):7302-10]

Jolkinolide B from Euphorbia fischeriana Steud Induces Apoptosis in Human Leukemic U937 Cells through PI3K/Akt and XIAP Pathways

“…It irreversibly inhibits IκB kinase and induces apoptosis of tumor cells (Yan et al, 2008). Furthermore, 17-Hydroxy-jolkinolide B strongly inhibits IL-6-induced as well as constitutive STAT3 activation, which inhibits growth and induces apoptosis of tumor cells (Wang et al, 2009). In the current study, we investigated the in vitro effects of Jolkinolide B on cell growth and death in U937 cells, human histiocytic lymphoma cell lines, and examined the mechanisms underlying its actions.…”

“…Euphorbia fischeriana Steud has long been used as a folk medicine to treat cancer in China. Early chemical investigation showed that the plant contains diterpenoids, triterpenoids and steroids including two ent-abietane diterpenoids, jolkinolide A and B, which exhibit significant antitumour activities against several tumour lines such as Sarcoma 180 and Ehrlich ascites carcinoma in mice (Wang et al, 2009). Previous study has shown that Jolkinolide B from the roots of Euphorbia fischeriana Steud could induce apoptosis in human chronic myeloid leukemia K562 cells (Luo, 2006).…”

Euphorbia Diterpenes: Isolation, Structure, Biological Activity, and Synthesis (2008–2012)

“…HJB has no activity on the platelet-derived and epidermal growth factor, or insulin-like growth factor 1 signalling pathways, therefore its effect is highly specific. 89 Yan et al investigated the antitumor effects of 17-acetoxyjolkinolide B and 6…”

Bigelovin inhibits STAT3 signaling by inactivating JAK2 and induces apoptosis in human cancer cells

“…Our results demonstrated that bigelovin inhibited JAK2 activity with an IC 50 of 44.24 Bigelovin inhibited JAK/STAT3 signaling in a thiol-dependent manner Bigelovin contains an α, β-unsaturated carbonyl group and an α-alkene-γ-lactone, which are reactive with thiols. Previous studies have shown that covalent modification of certain cysteine thiol groups of JAK2 by small molecule compounds could lead to JAK2 inactivation [31,32] . Therefore, we speculated that bigelovin may react with thiols of the cysteines in the JAK2 protein.…”