Genistein促進trichostatin A的抗腫瘤效果：體內研究

Abstract

In our previous in vitro studies, we found that genistein enhanced the apoptosis induced by trichostatin A (TSA), a novel anticancer drug, in human lung cancer cells; through up-regulation of tumor necrosis factor receptor-1 (TNFR-1) and histone acetylation. However, whether genistein exerts such effects in vivo is unclear. Thus, in the present study, using nude mice we performed a mouse xenograft experiment to investigate the enhancing effects of genistein on the antitumor effect of TSA in vivo. First, we investigated the distribution of genistein in nude mice. Genistein was administered to nude mice by gavage (OL: 20 mg/kgw or OH: 100 mg/kgw, 3 times/week) or by intraperitoneal injection (IPL:2 mg/kgw or IPH: 10 mg/kgw, 3times/week) for 12 weeks. After sacrificed the concentration of total genistein were determined. The results showed that the concentrations of total genistein in the plasma, lungs and livers of nude mice among groups were in an order: OH> OL, IPH> IPL. Secondly, the nude mice were subcutaneously injected in the right flank with A549 cells at a dose of 5 × 106 cells. Three weeks after cell injection, the animals were then randomly assigned to the following six groups (n = 5-7/group) for 15 weeks: tumor bearing group, TSA group, OG group, IG group, TSA+OG group, and TSA + IG group. TSA was given by intraperitoneal injection at a dose of 0.5 mg/kgw (2 times/week). Genistein was given by gavage (OG; 100 mg/kgw, 3 times/week) or by intraperitoneal (IG; 10 mg/kgw, 3 times/week). Tumor bearing group was given the vehicle only. The results showed that various treatments did not significantly affect the body weight of nude mice. Only TSA+IG treatment significantly decreased tumor volume as compared with tumor bearing group. Two hours after genistein administration, the total genistein concentrations in plasma of animals with OG treatment were higher than those with IG treatment. However, the total genistein concentrations in tumors of animals with IG treatment were hither than those with OG treatment. Tumors from mice treated with TSA+IG had higher TNFR-1, acetyl histone H3 and H4 than did those from tumor bearing and TSA-treated mice; whereas, the effects of OG+TSA on these protein expression were not significant or lower than that of TSA+IG. TSA treatment significantly increased the levels of TNF-α in plasma and tumors as well as the level of thiobarbituric acid reactive substances (TBARs) in plasma. IG significantly decreased the rise of TNF-α and TBARs induced by TSA, while OG had no significantly effects. Taken together, these data demonstrated that genistein administered by intraperitoneal injection enhanced the antitumor effect of TSA in vivo. The mechanisms were associated with increasing the expression of TNFR-1 and acetyl histone H3/H4 in tumors.