Reversal Effect of Low-Intensity Ultrasound on Adriamycin-Resistant Human Hepatoma Cells In Vitro and In Vivo

The aim of this study was to determine whether the ultrasound, with a dosage that did not lead to acute and delayed inhibition, could potentiate the cytotoxicity of adriamycin to human hepatoma resistant cell line HepG2 both in vitro and in vivo. In order to determine whether low-intensity ultrasound could reverse resistance in adriamycin-resistant human hepatoma cell line HepG2/ADM in vitro, cells were subjected to a variable level of ultrasound. The results showed that survival rates were decreased in groups in which ultrasound and adriamycin were exerted. The same effect of low-intensity ultrasound was also observed in the xenograft tumor experiment. Furthermore, transmission electron microscope revealed the cavitation effects play the determining role in accelerating transmembrane transportation, suggesting that low-intensity ultrasound altered the cell membrane thus resulting in change in adriamycin uptake into HepG2/ADM cells. Further investigation of the underlying mechanisms showed that the reversal effect of low-intensity ultrasound on adriamycin-resistant human hepatoma cells was attributed to the downregulation of the multidrug resistant genes, MDR1 and MRP1, in both mRNA and protein expression. In addition, downregulation of MDR1 and MRP1 was detected in HepG2/ADM xenograft tumor treated with adriamycin and ultrasound. These observations suggest the use of ultrasound could increase cytotoxicity attributable to adriamycin in chemoresistant human hepatoma cancer cells. Ultrasound is a promising therapeutic modality for refractory hepatoma patients.