XZH-5 Inhibits STAT3 Phosphorylation and Enhances the Cytotoxicity of Chemotherapeutic Drugs in Human Breast and Pancreatic Cancer Cells

Aiguo Liu, Yan Liu, Zhigang Jin, Qun Hu, Li Lin, David Jou, Jing Yang, Zhenghu Xu, Hong Wang, Chenglong Li, Jiayuh Lin

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere46624
JournalPloS one
Volume7
Issue number10
DOIs
StatePublished - Oct 3 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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