Silibinin inhibits human bladder transitional-cell papilloma RT4 tumor xenograft growth in athymic nude mice

5500

Bladder cancer is the 5th most common U.S. cancer with 57,000 new cases expected in 2003. One approach to control bladder cancer could be growth inhibition by the administration of one or more non-toxic naturally occurring or synthetic agents. Silibinin is a naturally occurring flavanone, isolated from milk thistle (Silybum marianum) extract, and has been shown to possess cancer preventive and therapeutic potential against various cancers. It is safe and non-toxic at high doses in several animal and human studies. Here, for first time we report the in vivo antitumor efficacy of silibinin against human bladder transitional-cell papilloma RT4 tumor xenograft growth. RT4 tumor xenograft was implanted s.c. in athymic nude mice on day 1. From day 2 mice were fed with silibinin at 100 and 200 mg/kg body weight/day doses in saline, 5 days a week for 12 weeks. Inhibition in tumor xenograft growth was observed following silibinin treatment without any gross signs of toxicity in terms of body weight gain and diet consumption throughout the experiment. At the end of experiment, silibinin feeding showed 51-58% (P≤0.01) decrease in tumor volume/mouse and 44-49% (P<0.05) decrease in tumor weight/mouse as compared to saline control. Tumor samples were immunohistochemically analyzed for proliferation cell nuclear antigen (PCNA), TUNEL and CD31. In silibinin-fed animals, PCNA-positive cells were decreased by 18-29% (P<0.001) and apoptotic cells were increased by 4-5 fold (P<0.001) as compared to control tumors. In CD31 immunostaining, we observed that silibinin causes 26-34% (P<0.001) decrease in microvessel density in tumors. Together, these findings suggest that silibinin has the potential to inhibit human bladder transitional-cell cancer via inhibition of tumor cell proliferation, induction of apoptosis and a decrease in tumor vasculature; silibinin therefore warrants further investigation in other bladder carcinoma models and may have utility in treatment and prevention strategies for human bladder cancer.