Arterial instillation of rapamycin in treatment of rabbit hepatic xenograft tumors and its effects on VEGF, iNOS, HIF-1α, Bcl-2, Bax expression and microvessel density

Abstract

Hepatocellular carcinoma is one of the leading causes of malignant tumor related death word wide with poor prognosis. Chemotherapy and TACE are main treatment methods for advanced stage cases. Rapamycin, a macrolide compound that initially used to coat coronary stents, can inhibit the growth of a variety of cancer cells especially hepatocellular carcinoma. Twenty-four healthy adult New Zealand white rabbits underwent CT-guided puncture to prepare a model of VX2 liver xenograft tumor. The rabbits were randomly divided into four groups with six in each group and received the following treatments: APR-TACE1: arterial perfusion of high-dose rapamycin combined with TACE; APR-TACE2: arterial perfusion of low-dose rapamycin combined with TACE; TACE: TACE alone; and IVR-TACE: intravenous injection of rapamycin combined with TACE. Two weeks after TACE treatment, the rabbits received CT scan and DSA angiography examination, and then killed by air embolism. The non-necrotic region and surrounding tissues were obtained from the peripheral tumor for iNOS, HIF-1α, VEGF, Bcl-2, and Bax protein expression analysis. Protein expression of iNOS, HIF-1α, VEGF, and Bcl-2 in APR-TACE1 were significantly lower than those in groups APR-TACE2, TACE, and IVR-TACE ( p < 0.05). iNOS, HIF-1α, and VEGF in APR-TACE2 were lower than those in TACE ( p < 0.05). iNOS and VEGF in APR-TACE2 were significantly lower than those in IVR-TACE ( p < 0.05). iNOS in IVR-TACE was significantly lower than that in TACE ( p < 0.05). The expression levels of Bcl-2 and Bax were statistically significant between APR-TACE2 and TACE ( p < 0.05). The MVD of the tumor tissue in APR-TACE1 was lower than that of groups APR-TACE2, TACE, IVR-TACE with statistical difference ( p < 0.05). However, MVD of APR-TACE2 was lower than that of groups TACE, IVR-TACE with significant statistical difference ( p < 0.05). Arterial instillation of rapamycin+TACE in treatment of rabbit hepatic xenograft tumors can reduce tumor neovascularization and inhibit iNOS, HIF-1α, VEGF, Bcl-2, and Bax protein expression.