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 cross-linking 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]

Induction of tumor cell apoptosis has been recognized as a valid anticancer strategy. However, therapeutic selectivity between tumor and normal cells has always been a challenge. Here, we report a novel anti-cancer compound methyl 3-(4-nitrophenyl) propiolate (NPP) preferentially induces apoptosis in tumor cells through P450-catalyzed reactive oxygen species (ROS) production. A compound sensitivity study on multiple cell lines shows that tumor cells with high basal ROS levels, low antioxidant capacities, and p53 mutations are especially sensitive to NPP. Knockdown of p53 sensitized non-transformed cells to NPP-induced cell death. Additionally, by comparing NPP with other ROS inducers, we show that the susceptibility of tumor cells to the ROS-induced cell death is influenced by the mode, amount, duration, and perhaps location of ROS production. Our studies not only discovered a unique anticancer drug candidate but also shed new light on the understanding of ROS generation and function and the potential application of a ROS-promoting strategy in cancer treatment.

MicroRNAs (miRNAs) are powerful regulators of diverse biologic processes. However, the function of most miRNAs in angiogenesis remains elusive. In this study, we identified miR‐191–5p (miR‐191) as a potent inhibitor of blood vessel development. Transfection of human dermal microvascular endothelial cells with miR‐191 mimic (miR‐191m) inhibited their proliferation, migration, and tube formation. Moreover, vascular sprouting of miR‐191m–transfected mouse aortic rings was significantly reduced when compared with controls. Transfection with miR‐191 inhibitor (miR‐191i) induced proangiogenic effects. The anti‐ and proangiogenic activities of miR191m and −191i were further demonstrated in vivo. Additional molecular biologic analyses revealed that miR‐191m activates NF‐kB signaling by up‐regulating the mRNA expression of p65. miR‐191 also increased the mRNA levels of the antiangiogenic factors p21 and tissue inhibitor of metalloproteinase‐1 and reduced the expression of the proangiogenic factors eNOS and matrix metalloproteinase‐1 and −9. Blockade of NF‐kB activation with Bay 11–7082 reversed the antiangiogenic effects of miR‐191m. These findings indicate that miR‐191 effectively suppresses angiogenesis by activation of the NF‐kB signaling pathway.—Gu, Y., Ampofo, E., Menger, M. D., Laschke, M. W. miR‐191 suppresses angiogenesis by activation of NF‐kB signaling. FASEB J . 31, 3321–3333 (2017). www.fasebj.org

Tubeimoside-1 suppresses tumor angiogenesis by stimulation of proteasomal VEGFR2 and Tie2 degradation in a non-small cell lung cancer xenograft model

Nuclear factor-κB (NF-κB) is critically important for tumor cell survival, growth, angiogenesis, and metastasis. One of the key events in the NF-κB signaling is the activation of inhibitor of NF-κB kinase (IKK) in response to stimuli of various cytokines. We have identified 17-acetoxyjolkinolide B (17-AJB) from a traditional Chinese medicinal herb Euphorbia fischeriana Steud as a novel small-molecule inhibitor of IKK. 17-AJB effectively inhibited tumor necrosis factor-α–induced NF-κB activation and induced apoptosis of tumor cells. 17-AJB had no effect on binding of tumor necrosis factor-α to its receptor or on binding of NF-κB to DNA. It inhibited NF-κB nuclear translocation. Detailed analysis revealed that the direct target of 17-AJB was IKK. 17-AJB kept IKK in its phosphorylated form irreversibly. This irreversible modification of IKK inactivated its kinase activity, leading to its failure to activate NF-κB. The effect of 17-AJB on IKK was specific. It had no effect on other kinases such as p38, p44/42, and JNK. In addition, 17-AJB induced apoptosis in tumor cells. The effects of 17-AJB on apoptosis correlated with inhibition of expression of the NF-κB-regulated genes. Taken together, our data suggest that 17-AJB is a novel type NF-κB pathway inhibitor. Its unique interaction mechanism with IKK may render it a strong apoptosis inducer of tumor cells and a novel type anticancer drug candidate. [Mol Cancer Ther 2008;7(6):1523–32]