Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the most commonly diagnosed tumors worldwide and is known to be resistant to conventional chemotherapy. New therapeutic strategies are urgently needed for treating HCC. Osthole, a natural coumarin derivative, has been shown to have anti-tumor activity. However, the effects of osthole on HCC have not yet been reported.Methods and FindingsHCC cell lines were treated with osthole at various concentrations for 24, 48 and 72 hours. The proliferations of the HCC cells were measured by MTT assays. Cell cycle distribution and apoptosis were determined by flow cytometry. HCC tumor models were established in mice by subcutaneously injection of SMMC-7721 or Hepa1-6 cells and the effect of osthole on tumor growths in vivo and the drug toxicity were studied. NF-κB activity after osthole treatment was determined by electrophoretic mobility shift assays and the expression of caspase-3 was measured by western blotting. The expression levels of other apoptosis-related genes were also determined by real-time PCR (PCR array) assays. Osthole displayed a dose- and time-dependent inhibition of the HCC cell proliferations in vitro. It also induced apoptosis and caused cell accumulation in G2 phase. Osthole could significantly suppress HCC tumor growth in vivo with no toxicity at the dose we used. NF-κB activity was significantly suppressed by osthole at the dose- and time-dependent manner. The cleaved caspase-3 was also increased by osthole treatment. The expression levels of some apoptosis-related genes that belong to TNF ligand family, TNF receptor family, Bcl-2 family, caspase family, TRAF family, death domain family, CIDE domain and death effector domain family and CARD family were all increased with osthole treatment.ConclusionOsthole could significantly inhibit HCC growth in vitro and in vivo through cell cycle arrest and inducing apoptosis by suppressing NF-κB activity and promoting the expressions of apoptosis-related genes.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and accounts for about 5.6% of all tumors [1]
Osthole treatment inhibited the proliferation of all four HCC cell lines in a dose-dependent manner
There was no significant difference in drug sensitivity (IC50: 189.5 mM, 161.9 mM, 161.4 mM and 137.0 mM, respectively) between the four HCC cell lines
Summary
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and accounts for about 5.6% of all tumors [1]. Previous studies have shown that some natural chemopreventive agents can induce apoptosis of tumor cells and inhibit tumor growth, including HCC, both in vitro and in vivo [8,9,10,11,12,13,14]. Because of their selectivity of killing tumor cells and minimal toxicity comparing with conventional chemotherapies, they are becoming promising approaches for tumor treatments. Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed tumors worldwide and is known to be resistant to conventional chemotherapy. The effects of osthole on HCC have not yet been reported
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