Matrine enhances the anticancer effect of cisplatin against hepatocellular carcinoma xenografts in nude mice by influencing expression of survivin/caspase-3

Abstract

To investigate the effect and molecular mechanism of cisplatin (DDP) combined with Matrine (Ma;plant alkaloid) against hepatocellular carcinoma using a nude mouse model with xenografted human tumors. Twenty-four 6-week old male BALB/c nude mice were subcutaneously injected with HepG2 cells into the axilla, and randomly divided into four groups:control (NS) group,Ma treatment group,DDP treatment group and DDP+Ma combination treatment group. All treatments were delivered via intraperitoneal injection.Changes in whole body weights and tumor volume were assessed by before and after treatment measurements and plotting of growth curves. After 14 days of drug intervention, the mice were sacrificed for collection of tumor tissue and assessment of the tumor inhibition rates for each treatment. Affects on expression of survivin and caspase-3 were assessed by immunohistochemistry. ANOVA test and t-test were performed for the statistical analyses. The tumor inhibition rates for the various treatments were:37.5%,Ma alone;75.0% DDP alone;83.3%,DDP+Ma group DDP combined. The DDP+Ma-induced inhibition was significantly greater than that achieved wit Ma or DDP alone (both P less than 0.05). The average weight of the DDP+Ma group (21.5 g) was lower than that of the NS group (28.5 g) and the Ma group (26.67 g),but higher than that of the DDP group (17.33 g).In addition, the DDP+Ma group also showed more robust general health,as indicated by activity,participation in life routines and appetite,than the DDP group. The rate of positive staining for survivin expression in tumor tissues was significantly lower in the DDP+Ma group (19.58%+/-4.52%) than in the NS group (83.26%+/-15.56%), the Ma group (62.50%+/-8.09%), and the DDP group (38.67%+/-8.26%) (all P less than 0.05).In contrast, the rate of positive staining for Bax expression was significantly higher in the DDP+Ma group (78.26%+/-6.09%) than in the NS group (21.15%+/-3.68%), the Ma group (35.13%+/-10.57%), and the DDP group (65.88%+/-4.81%) (all P less than 0.05). Treatment with Ma alone or DDP alone is sufficient to inhibit the growth ofxenografted human hepatocellular carcinoma cells in nude mice. The DDP+Ma combination treatment,however,shows greater inhibitory effect,suggesting that Ma may enhance DDP's anticancer properties. The improved health status of mice treated with DDP+Ma suggests that Ma may reduce DDP toxicity. The mechanism underlying these beneficial treatment effects may involve modulation of survivin/caspase-3 expression and subsequent apoptosis.