Enhancement of apoptosis by aspirin combined with sorafenib in a highly metastatic murine model of human hepatocellular carcinoma

Abstract

Objective To investigate the effect of combination of sorafenib and aspirin on tumor apoptosis,tumor growth,lung metastasis and survival of tumor-beating nude mice in a highly metastatic xenograft murine model of human hepatocellular carcinoma (HCC) and explore the mechanism.Methods The Xenograft of a highly metastatic human HCC tumor (LCI-D20) was used to evaluate survival,primary tumor growth and lung metastasis after treatment with aspirin alone or in combination with sorafenib.Apoptosis of tumor cells in vivo was determined by the terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling assay (TUNEL).Results Tumor volumes were (4.76 ±0.51 ),( 1.41 ±0.08),(0.66±0.12) and (4.58 ±0.47) cm3 in control,serafenib,serafenib plus aspirin,and aspirin groups,respectively.Lung metastases were 189 ±21,96 ± 15,30 ± 17 and 92 ± 18 in four groups,and median survival was 72,98,112 and 80 days,respectively.Apoptosis rate was (2.6 ± 1.1 )％,(8.6 ±3.7)％,(24.3±6.9)％ and (6.8 ± 1.5)％ respectively in four groups.Combination of aspirin and sorafenib significantly decreased tumor volume ( P ＜ 0.05 ),inhibited number of lung metastases ( P ＜ 0.01 ),and prolonged survival (P ＜ 0.05 ) as compared with sorafenib alone group.Increased apoptosis of tumor cells (P ＜0.05 ) was observed by combination of aspirin and sorafenib.Nuclear factor-κB (NF-κB) was upregulated and IκBα was downregulated by sorafenib,which was reversed by combination of aspirin with sorafenib.Conclusion Aspirin significantly promoted apoptosis of tumor cells in combination with sorafenib through inhibiting sorafenib-induced NF-κB activation. Key words: Carcinoma,hepatocellular; Sorafenib; Aspirin; NF-κB