Molecular Mechanisms by Which a Fucus vesiculosus Extract Mediates Cell Cycle Inhibition and Cell Death in Pancreatic Cancer Cells.
Molecular Mechanisms by Which a Fucus vesiculosus Extract Mediates Cell Cycle Inhibition and Cell Death in Pancreatic Cancer Cells.
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DOI：
10.3390/md13074470
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发表时间：
2015-07-20
期刊：
影响因子：
5.4
通讯作者：
Kalthoff H
中科院分区：
文献类型：
--
作者：
Geisen U;Zenthoefer M;Peipp M;Kerber J;Plenge J;Managò A;Fuhrmann M;Geyer R;Hennig S;Adam D;Piker L;Rimbach G;Kalthoff H
胰腺癌是最具侵袭性的癌症实体之一，5年生存率极低。因此，迫切需要具有特定作用模式的新型治疗剂。海洋生物是发现新的生物活性物质的一个有希望的来源。来自海洋藻类的次级代谢物特别令人感兴趣。本工作描述了细胞和分子机制诱导的HPLC分级，亲水性提取物来自波罗的海褐藻墨角藻水泡（Fv1）。用Fv 1处理导致对各种胰腺癌细胞系的活力的强烈抑制。该提取物由于细胞周期抑制剂的上调而抑制增殖细胞的细胞周期，这在mRNA（微阵列数据）和蛋白质水平上显示。结果，细胞以半胱天冬酶非依赖性方式死亡。非分裂细胞的实验表明，增殖是Fv 1有效性的先决条件。重要的是，Fv 1对非恶性静息T细胞和终末分化细胞（如红细胞）显示出低细胞毒性活性。有趣的是，与自噬抑制剂组合观察到加速的杀伤作用。我们的体外实验数据表明，Fv1可能是一个有前途的新代理，值得进一步发展，走向临床应用。
Pancreatic cancer is one of the most aggressive cancer entities, with an extremely poor 5-year survival rate. Therefore, novel therapeutic agents with specific modes of action are urgently needed. Marine organisms represent a promising source to identify new pharmacologically active substances. Secondary metabolites derived from marine algae are of particular interest. The present work describes cellular and molecular mechanisms induced by an HPLC-fractionated, hydrophilic extract derived from the Baltic brown seaweed Fucus vesiculosus (Fv1). Treatment with Fv1 resulted in a strong inhibition of viability in various pancreatic cancer cell lines. This extract inhibited the cell cycle of proliferating cells due to the up-regulation of cell cycle inhibitors, shown on the mRNA (microarray data) and protein level. As a result, cells were dying in a caspase-independent manner. Experiments with non-dividing cells showed that proliferation is a prerequisite for the effectiveness of Fv1. Importantly, Fv1 showed low cytotoxic activity against non-malignant resting T cells and terminally differentiated cells like erythrocytes. Interestingly, accelerated killing effects were observed in combination with inhibitors of autophagy. Our in vitro data suggest that Fv1 may represent a promising new agent that deserves further development towards clinical application.