Abstract
Prostate cancer is the most prevalent tumor found in men worldwide. Despite the efficiency of primary endocrine prostate cancer therapies, more efficient drugs are needed to tackle the most advanced and resistant forms of this condition. The present study investigated the antitumor effects of low-dose bufalin combined with hydroxycamptothecin on castration-resistant prostate cancer (CRPC) in mice, as well as the possible mechanisms of apoptosis induction. CRPC xenograft tumors were generated in mice and, subsequently, mice received appropriate doses of bufalin, hydroxycamptothecin or a combination of the two drugs. Tumors from each treatment group were removed, and the tumor volume, weight and inhibition rate of each group was determined. Hematoxylin and eosin staining was performed for pathological analysis and TUNEL staining was used to assess the level of apoptosis in the xenografts. Immunohistochemistry was used for the analysis of proliferating cell nuclear antigen expression and the expression of Bax, Bcl-XL, p53, programmed cell death 4 (PDCD4), phosphorylated (p)-AKT and glycogen synthase kinase (GSK)-3β was determined by western blotting. Treatment with bufalin significantly (P<0.05) reduced tumor volumes compared with the negative control group, reducing tumor volumes to lower levels when combined with hydroxycampothecin. The combination of bufalin (0.6 or 0.8 mg/kg) and hydroxycampothecin significantly (P<0.05) induced higher levels of cell apoptosis compared with the administration of bufalin or hydroxycampothecin alone. The combination of bufalin and hydroxycampothecin also increased the expression of apoptosis-related proteins Bax, p53, PDCD4 and GSK-3β, and decreased the expression of Bcl-XL and p-AKT compared with a single drug treatment. The present study suggested that the combination of bufalin and hydroxycampothecin improved the inhibitory effects of both drugs on CRPC tumors in vivo, potentially via the regulation of the PI3K/AKT/GSK-3β and p53-dependent apoptosis signaling pathways.