title: IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-κB activation.
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.
authors.affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Leo Lap-Yan
authors.initials: LL
authors.lastname: Wong
authors.forename: Ian Pak-Yan
authors.initials: IP
authors.lastname: Lam
authors.forename: Tracy Yuk-Nar
authors.initials: TY
authors.lastname: Wong
authors.forename: Wai-Lung
authors.initials: WL
authors.lastname: Lai
authors.forename: Heong-Fai
authors.initials: HF
authors.lastname: Liu
authors.forename: Lam-Lung
authors.initials: LL
authors.lastname: Yeung
authors.forename: Yick-Pang
authors.initials: YP
authors.lastname: Ching
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004220:Disulfides / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009284:Naphthols / Q000494:pharmacology*; D021381:Protein Transport; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D004220:Disulfides; C541795:IPA-3 compound; D016328:NF-kappa B; D009284:Naphthols; D054462:p21-Activated Kinases
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