Butanol fraction containing berberine or related compound from nexrutine inhibits NFkappaB signaling and induces apoptosis in prostate cancer cells.
Butanol fraction containing berberine or related compound from nexrutine inhibits NFkappaB signaling and induces apoptosis in prostate cancer cells.
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DOI：
10.1002/pros.20899
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发表时间：
2009-04-01
期刊：
影响因子：
2.8
通讯作者：
Kumar, Addanki P.
中科院分区：
文献类型：
--
作者：
Muralimanoharan, Sri Balasubashini;Kunnumakkara, A. B.;Shylesh, Bhaskaran;Kulkarni, Kaustubh H.;Haiyan, Xu;Ming, Hu;Aggarwal, Bharat B.;Rita, Ghosh;Kumar, Addanki P.
流行病学和实验室研究支持几种植物成分影响前列腺癌发生的假设，并有望预防疾病。之前我们报道了Nexrutine®（黄柏树皮提取物）通过调节Akt信号通路抑制转基因小鼠前列腺腺癌（TRAMP）模型中前列腺癌细胞的增殖和前列腺肿瘤的发展。在目前的研究中，我们进行了进一步的研究，以确定Nexrutine®的作用机制，并确定与其生物活性相关的有效成分。在这些研究中，研究人员使用了来自饲喂耐旭定®的TRAMP小鼠的雄激素响应性、雄激素非依赖性的人前列腺癌细胞系和组织。通过增殖试验、凋亡试验（DAPI和TUNEL染色）、瞬时转染、凝胶转移试验和Western blotting，鉴定了重现耐克鲁肽活性的丁醇部分。采用丁醇部分超高效液相色谱法（UPLC）对耐克鲁替尼的有效成分进行鉴定。丁醇部分重现了耐克鲁肽（Nexrutine®）抑制增殖的活性；（ii）诱导细胞凋亡；（iii）调节前列腺癌细胞中NFκB的转录活性。我们的数据还表明，Nexrutine®和丁醇组分通过抑制i - κ b α磷酸化来调节nf - κ b的转录活性。p65和磷酸化的i - κ b α在TRAMP小鼠肿瘤中高表达。相比之下，日粮给药耐克鲁汀可降低p65和磷酸化i - κ b α在TRAMP小鼠前列腺中的表达。此外，我们还利用UPLC在丁醇馏分中鉴定出了小檗碱或与其密切相关的化合物。结果提示，小檗碱或丁醇组分的密切相关成分可能在体外和体内通过靶向关键的细胞生存信号通路，参与观察到的前列腺癌细胞的生物学活性并诱导细胞凋亡。
Epidemiological and laboratory studies support the hypothesis that several plant components influence prostate carcinogenesis and holds promise for disease prevention. Previously we reported that Nexrutine® (bark extract from Phellodendron amurense) inhibits proliferation of prostate cancer cells and prostate tumor development in the transgenic adenocarcinoma of mouse prostate (TRAMP) model through modulation of Akt signaling pathway. In the present investigation we conducted studies to further define the mechanism of action of Nexrutine® and to identify the active component associated with its biological activity. Androgen-responsive, androgen-independent human prostate cancer cell lines and tissues from TRAMP mice fed Nexrutine® were used in these studies. Activity guided fractionation identified butanol fraction recapitulating the activities of Nexrutine® assessed by proliferation assays, apoptotic assays (DAPI and TUNEL staining), transient transfections, gel shift assays and Western blotting. In addition ultra-performance liquid chromatography (UPLC) of butanol fraction was used to identify active component of Nexrutine®. Butanol fraction recapitulated the activities of Nexrutine® in (i) inhibiting proliferation; (ii) inducing apoptosis; and (iii) modulating transcriptional activity of NFκB in prostate cancer cells. Our data also indicates that both Nexrutine® and butanol fraction modulates NFκB transcriptional activity by inhibiting IκBα phosphorylation. Expression of p65 and phosphorylated IκBα are high in tumors from TRAMP mice. In contrast dietary administration of Nexrutine® reduced expression of p65 and phosphorylated IκBα in prostate from TRAMP mice. In addition using UPLC, we have identified berberine or closely related compound in the butanol fraction. The results suggest that berberine or closely related component of butanol fraction may be responsible for the observed biological activities and induce apoptosis in prostate cancer cells by targeting critical cell survival signaling pathways both in vitro and in vivo.
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