SD-1029 Inhibits Signal Transducer and Activator of Transcription 3 Nuclear Translocation

Abstract

Purpose: Signal transducer and activator of transcription 3 (Stat3) proteins have important roles in cancer cell survival and proliferation. Recent studies show that aberrant Stat3 activation promotes tumor growth and survival in several human cancers, and thus, presents an attractive pathway for the development of targeted anticancer therapy. Stat3 is a DNA-binding transcription factor, and thus, its function depends on cytoplasmic to nuclear translocation. To discover novel inhibitors of the Stat3 signaling pathway, we designed a cell-based screening assay capable of identifying compounds that inhibit Stat3 nuclear translocation and activity. Experimental Design: Cell-based fluorescence microscope screening and quantitative measurement of enhanced green fluorescent protein^Stat3 nuclear translocation assays were used to identify novel Stat3 inhibitors. The effects of identified Stat3 inhibitors on Janus kinase (Jak), Stat3 expression, and activation were determined by Western blotting and kinase in vitro autophosphorylation assay. The effects of identified Stat3 inhibitors on cell growth was evaluated by cell proliferation assay and apoptosis assay.

LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model

“…There have been several strategies to inhibit the STAT3 pathway as a therapeutic approach in treating cancers, such as by using small molecules and DNA decoys (Lui et al, 2007). In addition, other inhibitors of STAT3 have also been reported including Cucurbitacin Q, which inhibits STAT3 phosphorylation (Sun et al, 2005), E804 that inhibits both Src and STAT3 (Nam et al, 2005); Stattic (Schust et al, 2006) and S3I-201 (Siddiquee et al, 2007), which inhibit STAT3 dimerisation, and SD-1029, which inhibits STAT3 nuclear translocation (Duan et al, 2006). One difficulty with targeting proteins directly is that the targeted proteins may often also control other vital pathways sometimes leading to severe unwanted effects.…”

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

“…The large body of data validating Stat3 as a potential target for cancer therapy, and the tolerance of normal cells to the loss of Stat3 function, has driven the effort to identify molecules capable of Stat3 inhibition (17,25). SD-1029 has been identified as a novel inhibitor of Stat3 activation (26). This molecule blocks Jak activity with resultant inhibition of Stat3 phosphorylation, nuclear transport, and a decrease in Stat3-dependent transcription.…”

“…This molecule blocks Jak activity with resultant inhibition of Stat3 phosphorylation, nuclear transport, and a decrease in Stat3-dependent transcription. Such actions have culminated in apoptosis in several human breast and ovarian cancer cell lines (26). The activation of Stat3 in chordomas indicates that this pathway may also serve as a potential target for the treatment of these tumors.…”

“…The Stat3 inhibitor SD-1029 was obtained through the National Cancer Institute (identifier: NSC 371488; ref. 26). In vitro cytotoxicity assays were done by MTT assay (Sigma) as described previously by Yang et al (29).…”

The tumor suppressor geneARHI(DIRAS3)inhibits ovarian cancer cell migration through multiple mechanisms

“…whereas phosphorylated, activated STAT3 translocates to the nucleus to induce gene transcription. 35 Nuclear STAT3 has been found in 70% of ovarian cancers, and is associated with a poor prognosis. 1 Our group has demonstrated that re-expression of ARHI at physiological levels in two different ovarian cancer cell lines inhibited nuclear translocation of STAT3 and suppressed motility.…”