Abstract 4429: An investigation on p21-activated protein kinase 1 inhibitor, IPA-3, in hepatocellular carcinoma

Abstract

Abstract Background: Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to metastasis and tumor recurrence. However, apart from Sorafenib, there is no proven effective systemic chemotherapy for HCC yet. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is commonly found in HCC, which is coupled with a more aggressive tumor behavior. In this study, we examined the effect of an allosteric inhibitor of PAK1, IPA-3, on hepatocarcinogenesis. Methods: Human HCC line H2M was treated with various dosages of IPA-3 or vehicle control in order to measure the phospho-PAK1 level. The cells were also subjected to different functional assays, including proliferation assay, transwell assay and colony formation assay, to examine the anti-cancer effect of IPA-3. Tumor xenografts in nude mice were used to examine the in vivo activity of IPA-3. Results: Pretreatment with IPA-3 dose-dependently suppressed fetal bovine serum (FBS)-, and tumor necrosis factor (TNF)-α-induced PAK1 activity. The inhibitory effect was causally accompanied with suppression on cell migration, and enhancement of cell spreading. Furthermore, IPA-3 treatment on HCC cell line demonstrated a suppression of cell growth. The concomitant increase in apoptosis and delay in DNA synthesis had suggested a mechanism explaining the inhibition of HCC proliferation. In vivo, intraperitoneal administration of IPA-3 to subcutaneous xenograft mouse model significantly reduced the tumor growth rate. Conclusion: Taken together, these data showed that IPA-3 restrains cancer cell tumorigenicity and metastasis, thus, suggesting the potential use of IPA-3 in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4429. doi:1538-7445.AM2012-4429