Sophoraflavanone G induces apoptosis of human cancer cells by targeting upstream signals of STATs

Kim, Byung Hak; Won, C.; Lee, Yun Han; Choi, Jun Young; Noh, Kum Hee; Han, Songhee; Lee, Haeri; Lee, Chang Seok; Lee, Dong Sup; Ye, Sang Kyu; Kim, Myoung-Hwan

doi:10.1016/j.bcp.2013.08.009

Cited by 30 publications

(17 citation statements)

References 60 publications

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“…Nevertheless, taken together, our data indicate that α-Br-TMC is able to target multiple pathways controlling inflammation, proliferation and survival. The natural compound sophoraflavanone G was recently reported to exhibit a similar pleiotropic activity against both the JAK/STAT signaling pathway and pathways controlling inflammation and infection in murine and human cell lines [36]. Since interconversion between flavanones and 2′-OH-chalcones was recently evidenced in cell culture [76], it might explain why these two classes of molecules exhibit similar biological activities.…”

Section: Discussionmentioning

confidence: 99%

The Synthetic α-Bromo-2′,3,4,4′-Tetramethoxychalcone (α-Br-TMC) Inhibits the JAK/STAT Signaling Pathway

et al. 2014

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Signal transducer and activator of transcription STAT5 and its upstream activating kinase JAK2 are essential mediators of cytokine signaling. Their activity is normally tightly regulated and transient. However, constitutive activation of STAT5 is found in numerous cancers and a driving force for malignant transformation. We describe here the identification of the synthetic chalcone α-Br-2′,3,4,4′-tetramethoxychalcone (α-Br-TMC) as a novel JAK/STAT inhibitor. Using the non-transformed IL-3-dependent B cell line Ba/F3 and its oncogenic derivative Ba/F3-1*6 expressing constitutively activated STAT5, we show that α-Br-TMC targets the JAK/STAT pathway at multiple levels, inhibiting both JAK2 and STAT5 phosphorylation. Moreover, α-Br-TMC alters the mobility of STAT5A/B proteins in SDS-PAGE, indicating a change in their post-translational modification state. These alterations correlate with a decreased association of STAT5 and RNA polymerase II with STAT5 target genes in chromatin immunoprecipitation assays. Interestingly, expression of STAT5 target genes such as Cis and c-Myc was differentially regulated by α-Br-TMC in normal and cancer cells. While both genes were inhibited in IL-3-stimulated Ba/F3 cells, expression of the oncogene c-Myc was down-regulated and that of the tumor suppressor gene Cis was up-regulated in transformed Ba/F3-1*6 cells. The synthetic chalcone α-Br-TMC might therefore represent a promising novel anticancer agent for therapeutic intervention in STAT5-associated malignancies.

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Section: Discussionmentioning

confidence: 99%

The Synthetic α-Bromo-2′,3,4,4′-Tetramethoxychalcone (α-Br-TMC) Inhibits the JAK/STAT Signaling Pathway

et al. 2014

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“…Anti-inflammatory and cytotoxic components of Sophora flavescens and Heterosmilacis Japonica have previously been identified [25,26,28,30,42–44]. The inhibitory concentrations for these individual compounds depends on the cell type being targeted, but tend to require greater than 1.2 mg/ml, which is at least twice the concentration of FKI required to limit S-180 cell growth in vitro .…”

Section: Discussionmentioning

confidence: 99%

Fufang Kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via TRPV1 signaling pathways

et al. 2014

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Cancer pain is a deleterious consequence of tumor growth and related inflammation. Opioids and antiinflammatory drugs provide first line treatment for cancer pain, but both are limited by side effects. Fufang Kushen injection (FKI) is GMP produced, traditional Chinese medicine used alone or with chemotherapy to reduce cancer-associated pain. FKI limited mouse sarcoma growth both in vivo and in vitro, in part, by reducing the phosphorylation of ERK and AKT kinases and BAD. FKI inhibited TRPV1 mediated capsaicin-induced ERK phosphorylation and reduced tumor-induced proinflammatory cytokine production. Thus, FKI limited cancer pain both directly by blocking TRPV1 signaling and indirectly by reducing tumor growth.

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“…Tyrosine residues on STAT proteins are phosphorylated by various upstream signaling cascades, including JAKs, Src, PI3K/Akt, and MAPKs [20]. To determine whether the inhibitory effect of alantolactone on STAT3 phosphorylation is due to the suppression of upstream signaling pathways, we evaluated the effects of alantolactone on the activation of JAK1, JAK2, and Src in MDA-MB-231 cells.…”

Section: Tyrosine Phosphatase Inhibitor Abrogates Alantolactone-inducmentioning

confidence: 99%

Alantolactone selectively suppresses STAT3 activation and exhibits potent anticancer activity in MDA-MB-231 cells

et al. 2015

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The important goal of cancer drug discovery is to develop therapeutic agents that are effective, safe, and affordable. In the present study, we demonstrated that alantolactone, which is a sesquiterpene lactone, has potential activity against triple-negative breast cancer MDA-MB-231 cells by suppressing the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Alantolactone effectively suppressed both constitutive and inducible STAT3 activation at tyrosine 705. Alantolactone decreased STAT3 translocation to the nucleus, its DNA-binding, and STAT3 target gene expression. Alantolactone significantly inhibits STAT3 activation with a marginal effect on MAPKs and on NF-κB transcription; however, this effect is not mediated by inhibiting STAT3 upstream kinases. Although SHP-1, SHP-2, and PTEN, which are protein tyrosine phosphatases (PTPs), were not affected by alantolactone, the treatment with a PTP inhibitor reversed the alantolactone-induced suppression of STAT3 activation, indicating that PTP plays an important role in the action of alantolactone. Finally, alantolactone treatment resulted in the inhibition of migration, invasion, adhesion, and colony formation. The in vivo administration of alantolactone inhibited the growth of human breast xenograft tumors. These results provide preclinical evidence to continue the development of alantolactone as a STAT3 inhibitor and as a potential therapeutic agent against breast cancer.

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Sophoraflavanone G induces apoptosis of human cancer cells by targeting upstream signals of STATs

Cited by 30 publications

References 60 publications

The Synthetic α-Bromo-2′,3,4,4′-Tetramethoxychalcone (α-Br-TMC) Inhibits the JAK/STAT Signaling Pathway

The Synthetic α-Bromo-2′,3,4,4′-Tetramethoxychalcone (α-Br-TMC) Inhibits the JAK/STAT Signaling Pathway

Fufang Kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via TRPV1 signaling pathways

Alantolactone selectively suppresses STAT3 activation and exhibits potent anticancer activity in MDA-MB-231 cells

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