Suppression of the growth of subcutaneous transplanted human liver cancer and lung metastasis in nude mice treated by sorafenib combined with fluorouracil / 中华肿瘤杂志

ABSTRACT

<p><b>OBJECTIVE</b>The aim of this study was to explore the inhibitory effect of sorafenib and 5-Fu on transplanted human liver cancer in nude mice, and to investigate the synergistic effect and mechanism between sorafenib and 5-Fu.</p><p><b>METHODS</b>The nude mouse model of human liver cancer was made by transplantation of human highly metastatic liver cancer cell line HCCLM3 cells, and the tumor-bearing nude mice were treated with sorafenib, 5-Fu or both, respectively, and mock-treated tumor-bearing nude mice as negative control. To assess the anti-tumor effect of sorafenib and the synergistic effect of sorafenib combined with 5-Fu by measuring the tumor weight and number of lung metastases. Moreover, the expressions of phosphorylated extracellular signal-regulated kinase (p-ERK), P-glycoprotein (P-gp) and topoisomerase 2-alpha (Topo IIa) in the nude mice were assayed by immunocytochemistry and Western blot.</p><p><b>RESULTS</b>The tumor weights and numbers of lung metastases were (2.7 ± 0.825) g and 12.714 ± 6.317 in the negative control group, (0.933 ± 0.333) g and 4.333 ± 3.983 in the sorafenib group, (0.786 ± 0.212) g and 5.429 ± 4.315 in the Sorafenib + 5-Fu combination group, and (2.438 ± 0.793) g and 10.429 ± 6.241 in the 5-Fu group. Statistically, the tumor weights and numbers of lung metastases in the sorafenib group and combination group were significantly decreased, compared with that in the control group (P < 0.05). There was no significant difference in the tumor weight and number of lung metastases between the sorafenib group and the combination treatment group (P > 0.05). The expression levels of p-ERK, P-gp and Topo IIa proteins in the tumors after normalization were negative control (0.017 ± 0.010, 0.085 ± 0.012, 0.103 ± 0.093), sorafenib group (0.010 ± 0.008, 0.044 ± 0.020, 0.020 ± 0.018), combination group (0.011 ± 0.007, 0.043 ± 0.023, 0.062 ± 0.026), and 5-Fu group (0.018 ± 0.009, 0.063 ± 0.032, 0.065 ± 0.034), respectively. Statistically, the expression of p-ERK, P-gp and Topo IIa in the Sorafenib group was significantly reduced compared with that of the control group (P < 0.05), and there was no significant difference in the expression of p-ERK, P-gp and Topo IIa between the sorafenib group and the combination treatment group (P > 0.05).</p><p><b>CONCLUSIONS</b>Sorafenib can inhibit not only the tumor growth and lung metastsis in the nude mouse models, but also reduce the expression of multidrug resistance proteins P-gp and Topo IIa as well. There is no significant advantage for the sorafenib + 5-Fu combination treatment than Sorafenib alone in inhibiting the expression of p-ERK, P-gp and Topo IIa.</p>