The marine natural product microsclerodermin A is a novel inhibitor of the nuclear factor kappa B and induces apoptosis in pancreatic cancer cells.
The marine natural product microsclerodermin A is a novel inhibitor of the nuclear factor kappa B and induces apoptosis in pancreatic cancer cells.
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DOI：
10.1007/s10637-014-0185-3
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发表时间：
2015-02
影响因子：
3.4
通讯作者：
Wright AE
中科院分区：
文献类型：
--
作者：
Guzmán EA;Maers K;Roberts J;Kemami-Wangun HV;Harmody D;Wright AE
胰腺癌是美国癌症死亡的第四大原因，对目前所有的化疗都具有高度耐药性，慢性炎症会促进其生长。炎症的重要介质是核因子 kappa B (NFκB)，它是一种转录因子，可调节 500 多个基因，包括抗凋亡蛋白、细胞周期进程和细胞因子产生的调节。 NFκB 在胰腺癌细胞中持续激活，有助于其抵抗细胞凋亡和高转移潜力。尽管已经鉴定出许多抑制 NFκB 的小分子，但目前尚未在临床中使用，这可能是由于它们缺乏特异性。为了鉴定新型 NFκB 抑制剂，使用在 NFκB 转录控制下产生荧光素的报告细胞系筛选海洋生物富集组分的 HBOI 文库。来自海绵 Amphibleptula 的级分在此筛选中具有活性，并含有抗真菌环肽 microsclerodermin A。此处显示 Microsclerodermin A 可抑制报告细胞系中的 NFκB 转录活性，降低 AsPC-1 细胞系中磷酸化（活性）NFκB 的水平，在低微摩尔范围内对 AsPC-1、BxPC-3、MIA 具有 IC50 细胞毒性PaCa-2 和 PANC-1 胰腺癌细胞系，并诱导 AsPC-1、BxPC-3 和 PANC-1 细胞系显着凋亡。用微硬皮素 A 处理 AsPC-1 细胞也导致 IL-8 产量增加，但没有明显诱导血管生成因子，并且微硬皮素 A 对 NFκB 的抑制可能是由糖原合酶激酶 3β 途径介导的。
Pancreatic cancer, the 4th leading cause of cancer death in the US, is highly resistant to all current chemotherapies, and its growth is facilitated by chronic inflammation. An important mediator of inflammation is the nuclear factor kappa B (NFκB), a transcription factor that regulates over 500 genes including the regulation of anti-apoptotic proteins, cell cycle progression and cytokine production. NFκB is constitutively activated in pancreatic cancer cells contributing to their resistance to apoptosis and high metastatic potential. Although many small molecules that inhibit NFκB have been identified, none are currently used in the clinic, perhaps due to their lack of specificity. To identify novel inhibitors of NFκB, the HBOI library of enriched fractions from marine organisms was screened using a reporter cell line that produces luciferin under the transcriptional control of NFκB. Fractions from the sponge Amphibleptula were active in this screen and contained the antifungal cyclic peptide microsclerodermin A. Microsclerodermin A is shown here to inhibit NFκB transcriptional activity in a reporter cell line, to reduce levels of phosphorylated (active) NFκB in the AsPC-1 cell line, to have an IC50 for cytotoxicity in the low micromolar range against the AsPC-1, BxPC-3, MIA PaCa-2 and PANC-1 pancreatic cancer cell lines, and to induce significant apoptosis in the AsPC-1, BxPC-3 and the PANC-1 cell lines. Treatment of AsPC-1 cells with microsclerodermin A also resulted in an increase in IL-8 production without apparent induction of angiogenic factors and there is the possibility that inhibition of NFκB by microsclerodermin A is mediated by the glycogen synthase kinase 3β pathway.