Radiosensitization by combining an aurora kinase inhibitor with radiotherapy in hepatocellular carcinoma through cell cycle interruption

Abstract

Radiotherapy has been integrated into the multimodal treatment of hepatocellular carcinoma (HCC), especially of localized hepatic tumor(s) refractory to conventional treatment. However, tumor control remains unsatisfactory mainly because of insufficient dose, and sublethally irradiated tumor may associate with metastasis. Our aim was to assess the effect of combining a molecularly targeted Aurora kinase inhibitor, VE-465, with radiotherapy in in vitro and in vivo models of human HCC. Human HCC cell lines (Huh7 and PLC-5) were used to evaluate the in vitro synergism of combining VE-465 with irradiation. Flow cytometry analyzed the cell cycle changes, while western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with VE-465 and/or radiotherapy for the in vivo response. VE-465 significantly enhanced radiation-induced death in HCC cells by a mechanism involving the enhanced inhibition of histone H3 phosphorylation and interruption of cell cycle change. In SCID, mice bearing ectopic HCC xenografts, pretreatment with VE-465 (20 mg/kg/day × 9 days) significantly enhanced the tumor-suppressive effect of radiotherapy (5 Gy/day × 5 days) by 54.0%. A similar combinatorial effect of VE-465 and radiotherapy was observed in an orthotopic model of Huh7 tumor growth by 17.2%. In the orthotopic Huh7 xenografts, VE-465 significantly enhanced radiation-induced tumor growth suppression by a mechanism involving the increased apoptosis. VE-465 is a potent inhibitor of Aurora kinase with therapeutic value as a radiosensitizer of HCC. What's new? Inhibitors of Aurora kinases, key molecules in the maintenance of accurate cell cycling and genomic stability, have emerged as promising new antitumor agents. Here, the authors examined whether the pan-Aurora kinase inhibitor VE-465 sensitizes hepatocellular carcinomas (HCC) to radiation. Radiation is often suboptimal in HCC and increases the risk of metastasis. They show that combination of VE-465 with radiation results in synergistic inhibition of survival of HCC cell lines and the enhanced suppression of tumor growth in mice. These studies are promising but the authors caution that a careful analysis of malignant and neighboring nonmalignant tissue is required to conclusively evaluate the radiosensitizing effects of VE-465. © 2013 UICC.