Abstract
BackgroundUCN-01 (7-hydroxystaurosporine), a protein kinase inhibitor, has attracted a great deal of attention as a potent antitumour agent. Several clinical trials of UCN-01 alone or in combination with other agents for different tumour types are currently underway, and some of these trials have had positive results. Hepatocellular carcinoma has high incidence rates and is associated with poor prognosis and high mortality rates.MethodsThree different hepatoma cell lines (Huh7, HepG2, and Hep3B) were treated with different concentrations of UCN-01, and the anti-tumour effects of UCN-01 were evaluated. Following UCN-01 treatment, cell growth was measured using an MTT assay, cell cycle arrest was assayed using flow cytometry, and the mechanisms of cell cycle arrest and invasion inhibition were investigated through western blotting and a Matrigel invasion assay.ResultsAfter a 72-h UCN-01 treatment, the growth of different hepatoma cell lines was significantly inhibited in a dose-dependent manner, with IC50 values ranging from 69.76 to 222.74 nM. Flow cytometry results suggested that UCN-01 inhibits proliferation in the hepatoma cells by inducing S and G2/M phase arrest, but not G1/S arrest, which differs from previous reports that used other tumour cell lines. Western blot results illustrated that UCN-01 induces a G2/M phase arrest, regardless of the status of the p53/P21waf1 pathway, whereas the CHK2/CDC25C pathway and the p53/p21waf1 pathway were involved in the UCN-01-induced S phase arrest. UCN-01 remarkably inhibited Huh7 cell invasion in a time-dependent manner. Suppression of Huh7 cell invasion may be due to the down-regulation of phosphorylated β-catenin by UCN-01.ConclusionsThese findings suggest that UCN-01 induces hepatoma cell growth inhibition by regulating the p53/p21waf1 and CHK2/CDC25 pathways. Suppression of Huh7 cell invasion by UCN-01 may be due to the down-regulation of phosphorylated β-catenin. These data lend support for further studies on UCN-01 as a promising anti-HCC candidate.
Highlights
UCN-01 (7-hydroxystaurosporine), a protein kinase inhibitor, has attracted a great deal of attention as a potent antitumour agent
Huh7, HepG2, and Hep3B cells treated with UCN-01 for 72 h accumulated cells in the S and G2/M phases in a dose-dependent manner compared with untreated controls
UCN-01 induces cell cycle arrest in hepatoma cells via the p53/pP21waf1 and CHK2/CDC25C pathways To understand the mechanisms by which UCN-01 induces G2/M phase arrest, we studied intracellular signalling through western blot analyses (Figure 3)
Summary
UCN-01 (7-hydroxystaurosporine), a protein kinase inhibitor, has attracted a great deal of attention as a potent antitumour agent. Many conventional anticancer treatments kill cells irrespective of whether they are normal or cancerous; patients suffer adverse side effects due to healthy cell loss. For this reason, new anticancer drugs are required. UCN-01 (7-hydroxystaurosporine), both alone and in combination with chemotherapeutic agents and ionising radiation, is currently being evaluated in clinical trials as an antineoplastic agent [4]. UCN-01 has antiproliferative activity and is well tolerated both in vitro and in vivo This antiproliferative activity may be through protein kinase C inhibition [5]. UCN-01 can abrogate cell cycle arrest independent of p53 and p21waf1 [7,8,9]
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