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XZH-5 inhibits STAT3 phosphorylation and enhances the cytotoxicity of chemotherapeutic drugs in human breast and pancreatic cancer cells.

Liu A, Liu Y, Jin Z, Hu Q, Lin L, Jou D, Yang J, Xu Z, Wang H, Li C, Lin J
PLoS One. 2012 7 (10): e46624

PMID: 23056374 · PMCID: PMC3463519 · DOI:10.1371/journal.pone.0046624

Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in breast and pancreatic cancer. Inhibiting constitutive STAT3 signaling represents a promising molecular target for therapeutic approach. Using structure-based design, we developed a non-peptide cell-permeable, small molecule, termed as XZH-5, which targeted STAT3 phosphorylation. XZH-5 was found to inhibit STAT3 phosphorylation (Tyr705) and induce apoptosis in human breast and pancreatic cancer cell lines expressing elevated levels of phosphorylated STAT3. XZH-5 could also inhibit interleukin-6-induced STAT3 phosphorylation in cancer cell lines expressing low phosphorylated STAT3. Inhibition of STAT3 signaling by XZH-5 was confirmed by the down-regulation of downstream targets of STAT3, such as Cyclin D1, Bcl-2, and Survivin at mRNA level. In addition, XZH-5 inhibited colony formation, cell migration, and enhanced the cytotoxicity of chemotherapeutic drugs when combined with Doxorubicin or Gemcitabine. Our results indicate that XZH-5 may be a potential therapeutic agent for breast and pancreatic cancers with constitutive STAT3 signaling.

MeSH Terms (23)

Animals Apoptosis Blotting, Western Breast Neoplasms Cell Line, Tumor Cell Movement Cyclin D1 Female HeLa Cells Histidine Humans Inhibitor of Apoptosis Proteins Interleukin-6 Mice Mice, SCID Pancreatic Neoplasms Phenylurea Compounds Phosphorylation Proto-Oncogene Proteins c-bcl-2 Reverse Transcriptase Polymerase Chain Reaction STAT1 Transcription Factor STAT3 Transcription Factor Survivin

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