Gu Renze, Zhang Qingchuan
Department of Urology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
Exp Ther Med. 2021 Sep;22(3):1015. doi: 10.3892/etm.2021.10447. Epub 2021 Jul 15.
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 , potentially via the regulation of the PI3K/AKT/GSK-3β and p53-dependent apoptosis signaling pathways.
前列腺癌是全球男性中最常见的肿瘤。尽管原发性内分泌前列腺癌治疗方法有效，但仍需要更有效的药物来应对这种疾病最晚期和耐药的形式。本研究调查了低剂量蟾毒灵联合羟基喜树碱对小鼠去势抵抗性前列腺癌（CRPC）的抗肿瘤作用，以及诱导细胞凋亡的可能机制。在小鼠体内生成CRPC异种移植肿瘤，随后，小鼠接受适当剂量的蟾毒灵、羟基喜树碱或两种药物的组合。切除每个治疗组的肿瘤，测定每组的肿瘤体积、重量和抑制率。进行苏木精-伊红染色用于病理分析，TUNEL染色用于评估异种移植瘤中的细胞凋亡水平。免疫组织化学用于分析增殖细胞核抗原的表达，通过蛋白质印迹法测定Bax、Bcl-XL、p53、程序性细胞死亡4（PDCD4）、磷酸化（p）-AKT和糖原合酶激酶（GSK）-3β的表达。与阴性对照组相比, 蟾毒灵治疗显著（P<0.05）减小了肿瘤体积，与羟基喜树碱联合使用时肿瘤体积减小到更低水平。与单独给予蟾毒灵或羟基喜树碱相比，蟾毒灵（0.6或0.8mg/kg）与羟基喜树碱联合使用显著（P<0.05）诱导更高水平的细胞凋亡。与单一药物治疗相比，蟾毒灵与羟基喜树碱联合使用还增加了凋亡相关蛋白Bax、p53、PDCD4和GSK-3β 的表达，并降低了Bcl-XL和p-AKT的表达。本研究表明，蟾毒灵与羟基喜树碱联合使用可提高两种药物对CRPC肿瘤 的抑制作用，可能是通过调节PI3K/AKT/GSK-3β和p53依赖性凋亡信号通路实现的。
