Honokiol, a constituent of oriental medicinal herb Magnolia officinalis, inhibits growth of PC-3 xenografts in vivo in association with apoptosis induction
Honokiol, a constituent of oriental medicinal herb Magnolia officinalis, inhibits growth of PC-3 xenografts in vivo in association with apoptosis induction
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DOI：
10.1158/1078-0432.ccr-07-1926
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发表时间：
2008-02-15
影响因子：
11.5
通讯作者：
Singh, Shivendra V.
中科院分区：
文献类型：
--
作者：
Hahm, Eun-Ryeong;Arlotti, Julie A.;Singh, Shivendra V.
目的：本研究旨在确定和厚朴酚（东方药草厚朴的一种成分）在培养物和体内对人类前列腺癌细胞的功效。实验设计：通过分析细胞质组蛋白相关 DNA 片段来评估和厚朴酚介导的细胞凋亡。 Bax 和 Bak 蛋白的敲低是通过使用 siRNA 瞬时转染实现的。通过口服强饲法对雄性裸鼠皮下注射和厚朴酚。植入PC-3细胞。检查对照小鼠和和厚朴酚治疗小鼠的肿瘤切片的凋亡小体（末端脱氧核糖核苷酸转移酶介导的 dUTP 缺口末端标记测定）、增殖指数（增殖细胞核抗原染色）和新血管形成（CD31 染色）。通过免疫印迹法测定细胞裂解物和肿瘤上清液中 Bcl-2 家族蛋白的水平。结果：将人前列腺癌细胞（PC-3、LNCaP 和 C4-2）暴露于和厚朴酚会导致细胞凋亡 DNA 片段化，其浓度和时间依赖性，与雄激素反应性或 p53 状态无关。和厚朴酚诱导的细胞凋亡与 Bax、Bak 和 Bad 的诱导以及 Bcl-xL 和 Mcl-1 蛋白水平的降低相关。用 Bak 和 Bax 靶向 siRNA 以及 Bcl-xL 质粒瞬时转染 PC-3 细胞，可针对和厚朴酚诱导的细胞凋亡提供部分但显着的保护。每只小鼠口服 2 mg 和厚朴酚（每周三次）可显着延缓 PC-3 异种移植物的生长，但不会导致体重减轻。与对照肿瘤相比，经和厚朴酚治疗的小鼠肿瘤表现出明显更高的凋亡小体计数，并降低了增殖指数和新血管形成。结论：我们的数据表明，在传统东方医学中用于治疗各种疾病的和厚朴酚可能是治疗和/或预防人类前列腺癌的有吸引力的药物。
Purpose: This study was undertaken to determine the efficacy of honokiol, a constituent of oriental medicinal herb Magnolia officinalis, against human prostate cancer cells in culture and in vivo.Experimental Design: Honokiol-mediated apoptosis was assessed by analysis of cytoplasmic histone-associated DNA fragmentation. Knockdown of Bax and Bak proteins was achieved by transient transfection using siRNA. Honokiol was administered by oral gavage to male nude mice s.c. implanted with PC-3 cells. Tumor sections from control and honokiol-treated mice were examined for apoptotic bodies (terminal deoxyribonucleotidyl transferase - mediated dUTP nick end labeling assay), proliferation index (proliferating cell nuclear antigen staining), and neovascularization (CD31 staining). Levels of Bcl-2 family proteins in cell lysates and tumor supernatants were determined by immunoblotting.Results: Exposure of human prostate cancer cells (PC-3, LNCaP, and C4-2) to honokiol resulted in apoptotic DNA fragmentation in a concentration- and time-dependent manner irrespective of their androgen responsiveness or p53 status. Honokiol-induced apoptosis correlated with induction of Bax, Bak, and Bad and a decrease in Bcl-xL and Mcl-1 protein levels. Transient transfection of PC-3 cells with Bak- and Bax-targeted siRNAs and Bcl-xL plasmid conferred partial yet significant protection against honokiol-induced apoptosis. Oral gavage of 2 mg honokiol/mouse (thrice a week) significantly retarded growth of PC-3 xenografts without causing weight loss. Tumors from honokiol-treated mice exhibited markedly higher count of apoptotic bodies and reduced proliferation index and neovascularization compared with control tumors.Conclusion: Our data suggest that honokiol, which is used in traditional oriental medicine for the treatment of various ailments, may be an attractive agent for treatment and/or prevention of human prostate cancers.