Ruhr University of Bochum, Marienhospital Herne, Herne, Germany.
Phytomedicine. 2012 Nov 15;19(14):1298-306. doi: 10.1016/j.phymed.2012.08.004. Epub 2012 Sep 14.
The aim of this work was to characterize the antitumoral activity of the plant compound 7-epi-nemorosone in prostate carcinoma cell lines. Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men. In spite of the current therapeutic options for this cancer entity, many patients die due to metastases in distant organs and acquired chemotherapy resistance. Thus, approaches to provide improvements in outcome and quality of life for such patients are urgently needed. Recently, the polyisoprenylated benzophenone 7-epi-nemorosone, originally collected by honeybees from Clusia rosea and Clusia grandiflora (Clusiaceae), has been described to be a potent antitumoral agent. Here, its activity in prostate carcinoma is reported. 7-epi-nemorosone was isolated from Caribbean propolis employing RP-HPLC techniques. Its cytotoxicity was assessed using the MTT proliferation assay in human androgen-dependent prostate carcinoma LNCaP cells including an MDR1(+) sub-line. No cross-resistance was detected. FACS-based cell cycle analysis revealed a significant increase in the sub-G0/G1, G1, and depletion in the S phase populations. A concomitant down-regulation of cyclins D1/D3 and CDK 4/6 in LNCaP cells was detected by Western blot. Annexin-V-FITC labeling and caspase-3 cleavage assays showed that 7-epi-nemorosone induced apoptotic events. Major signal transduction elements such as p38 MAPK and Akt/PKB as well as androgen receptor AR and PSA production were found to be down-regulated after exposure to the drug. ERK1/2 protein levels and phosphorylation status were down-regulated accompanied by up-regulation but inhibition of the activity of their immediate upstream kinases MEK1/2. Additionally, Akt/PKB enzymatic activity was effectively inhibited at a similar concentration as for MEK1/2. Here, we demonstrate for the first time that 7-epi-nemorosone exerts cytotoxicity in an androgen-dependent prostate carcinoma entity by targeting the MEK1/2 signal transducer.
这项工作的目的是研究植物化合物 7-表-新莫罗斯酮在前列腺癌细胞系中的抗肿瘤活性。前列腺癌是最常见的恶性肿瘤，也是男性癌症死亡的第二大主要原因。尽管目前有针对这种癌症实体的治疗方法，但许多患者因远处器官转移和获得化疗耐药而死亡。因此，迫切需要提供改善此类患者预后和生活质量的方法。最近，从 Clusia rosea 和 Clusia grandiflora（Clusiaceae）的蜜蜂中收集到的多异戊二烯基二苯甲酮 7-表-新莫罗斯酮已被描述为一种有效的抗肿瘤剂。本文报道了其在前列腺癌中的活性。7-表-新莫罗斯酮采用反相高效液相色谱（RP-HPLC）技术从加勒比蜂胶中分离得到。采用 MTT 增殖测定法评估其对人雄激素依赖性前列腺癌 LNCaP 细胞（包括 MDR1(+)亚系）的细胞毒性。未检测到交叉耐药性。基于 FACS 的细胞周期分析显示，S 期细胞群显著减少，G0/G1 期和 G1 期细胞群增加。Western blot 检测到 LNCaP 细胞中环蛋白 D1/D3 和 CDK 4/6 的表达下调。Annexin-V-FITC 标记和 caspase-3 切割试验表明，7-表-新莫罗斯酮诱导了细胞凋亡。研究发现，药物作用后，主要信号转导元件如 p38 MAPK 和 Akt/PKB 以及雄激素受体 AR 和 PSA 的产生均下调。ERK1/2 蛋白水平及其磷酸化状态下调，同时其上游激酶 MEK1/2 的活性上调但被抑制。此外，Akt/PKB 的酶活性在与 MEK1/2 相似的浓度下被有效抑制。本研究首次证明，7-表-新莫罗斯酮通过靶向 MEK1/2 信号转导器在雄激素依赖性前列腺癌实体中发挥细胞毒性作用。
