Seo Seong Il, Gera Lajos, Zhau Haiyen E, Qian Wei Ping, Iqbal Shareen, Johnson Nicole A, Zhang Shumin, Zayzafoon Majd, Stewart John, Wang Ruoxiang, Chung Leland W K, Wu Daqing
Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, 1365-B C;ifton Road, Atlanta, GA 30322, USA.
Clin Cancer Res. 2008 Oct 1;14(19):6198-206. doi: 10.1158/1078-0432.CCR-08-1023.
Survivin overexpression has been associated with an unfavorable outcome in human PCa; however, its role in metastasis remains elusive. We aim to (a) evaluate the clinical implications of survivin expression in PCa bone metastasis; (b) determine in vivo efficacy of BKM1740, a small-molecule compound, against PCa skeletal growth and survival; and (c) investigate molecular mechanism by which BKM1740 augments apoptosis in bone metastatic PCa cells.
Survivin expression was analyzed in PCa specimens and experimental models. Bone metastatic C4-2 and ARCaP(M) cell lines were used to evaluate the in vitro effects of BKM1740 and molecular mechanism for the induction of apoptosis. C4-2 cells were grown intratibially in athymic nude mice to evaluate the in vivo efficacy of BKM1740. Tumor growth in mouse bone was assessed by serum prostate-specific antigen and radiography and confirmed by immunohistochemical analyses.
Survivin expression is positively associated with clinical PCa bone metastasis. BKM1740 induced apoptosis in PCa cells by repressing survivin. Mice with established C4-2 tumors in tibia showed a marked decrease in serum prostate-specific antigen and much improved bone architecture radiographically after treatment with BKM1740. Immunohistochemical assays of mouse tumor samples confirmed that the in vivo effects were mediated by inhibition of survivin and induction of apoptosis.
Survivin expression is associated with PCa bone metastasis. BKM1740 treatment specifically inhibited survivin and induced apoptosis in vitro and was efficacious in retarding PCa skeletal growth in a mouse model. BKM1740 is a promising small-molecule compound that could be used to treat PCa bone metastasis.
Survivin过表达与人类前列腺癌的不良预后相关；然而，其在转移中的作用仍不明确。我们旨在：（a）评估Survivin表达在前列腺癌骨转移中的临床意义；（b）确定小分子化合物BKM1740对前列腺癌骨骼生长和存活的体内疗效；（c）研究BKM1740增强骨转移性前列腺癌细胞凋亡的分子机制。
在前列腺癌标本和实验模型中分析Survivin表达。使用骨转移性C4-2和ARCaP（M）细胞系评估BKM1740的体外作用以及诱导凋亡的分子机制。将C4-2细胞接种于无胸腺裸鼠的胫骨内，以评估BKM1740的体内疗效。通过血清前列腺特异性抗原和X线摄影评估小鼠骨骼中的肿瘤生长，并通过免疫组织化学分析进行确认。
Survivin表达与临床前列腺癌骨转移呈正相关。BKM1740通过抑制Survivin诱导前列腺癌细胞凋亡。胫骨中已建立C4-2肿瘤的小鼠在接受BKM1740治疗后，血清前列腺特异性抗原显著降低，X线摄影显示骨骼结构明显改善。对小鼠肿瘤样本进行的免疫组织化学分析证实，体内作用是通过抑制Survivin和诱导凋亡介导的。
Survivin表达与前列腺癌骨转移相关。BKM1740治疗在体外特异性抑制Survivin并诱导凋亡，在小鼠模型中对延缓前列腺癌骨骼生长有效。BKM1740是一种有前景的小分子化合物，可用于治疗前列腺癌骨转移。
