IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-κB activation

PLoS One. 2013 Jul 19;8(7):e68843. doi: 10.1371/journal.pone.0068843. Print 2013.

Abstract

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to the high incidences of metastasis and tumor recurrence. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is frequently observed in HCC and is associated with a more aggressive tumor behavior, suggesting that PAK1 is a potential therapeutic target in HCC. In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. Using cell proliferation, colony formation and BrdU incorporation assays, we demonstrated that IPA-3 treatment significantly inhibited the growth of HCC cells. The mechanisms through which IPA-3 treatment suppresses HCC cell growth are enhancement of apoptosis and blockage of activation of NF-κB. Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells. Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells. Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Disulfides / pharmacology*
  • Enzyme Activation / drug effects
  • Humans
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology*
  • Male
  • NF-kappa B / metabolism*
  • Naphthols / pharmacology*
  • Protein Transport
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • p21-Activated Kinases / metabolism*

Substances

  • Disulfides
  • IPA-3 compound
  • NF-kappa B
  • Naphthols
  • p21-Activated Kinases

Grant support

This work was supported by the Hong Kong Research Fund for the Control of Infectious Disease (No. 09080782) and the Hong Kong Research Grant Council (HKU 7/CRF/09), The University of Hong Kong (Small Project Funding 201109176021 to LLY Wong and YP Ching). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.