Effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway.

BACKGROUND AND AIM: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and is used to reduce cancer-induced osteolysis. We reported previously that ZOL delayed both the growth and pain progression of bone metastases from hepatocellular carcinoma. The present study was designed to evaluate the effects of ZOL on hepatoma cell lines and the molecular mechanisms of such effects.

METHODS

Cell viability assay, scratch assay, immunohistochemistry, Western blotting, and flow cytometry analysis were performed using Huh7 and HepG2 cells treated with and without ZOL.

RESULTS

ZOL reduced cell growth in a dose-dependent manner and prevented cell migration when used at a concentration exceeding 10 μM. Immunohistochemistry showed that the inhibitory effects of ZOL on hepatoma cell progression was not due to the suppression of Ras and RhoA expression but due to inhibition of their translocation from the cytosol to the cell membrane, which terminates mevalonate pathway. Immunoblotting and flow cytometry showed that ZOL inhibited the mitogen-activated protein kinase pathway (MAPK) and induced apoptosis of hepatoma cells.

CONCLUSIONS

Our results indicated that ZOL prevented cell growth and metastasis based on direct antitumor effects in hepatoma cells. The use of ZOL could not only suppress the progression to bone metastatic lesions but also prevented growth of primary hepatocellular carcinoma.