Inhibition of IL-8 secretion on BxPC-3 and MIA PaCa-2 cells and induction of cytotoxicity in pancreatic cancer cells with marine natural products.
Inhibition of IL-8 secretion on BxPC-3 and MIA PaCa-2 cells and induction of cytotoxicity in pancreatic cancer cells with marine natural products.
复制标题
抑制IL-8对BXPC-3和MIA PACA-2细胞的分泌以及用海洋天然产物诱导胰腺癌细胞中细胞毒性的诱导。
DOI：
10.1097/cad.0000000000000443
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发表时间：
2017-02
影响因子：
2.3
通讯作者：
Wright AE
中科院分区：
文献类型：
--
作者：
Guzmán EA;Harmody D;Pitts TP;Vera-Diaz B;Winder PL;Yu Y;Wright AE
胰腺癌是所有癌症中预后最差的癌症之一，因为通常在患者确诊时就已经转移了。美国癌症协会（American Cancer Society）估计，93%的患者将在确诊后的五年内死亡，这凸显了对治疗这种疾病的新药的需求。白细胞介素8 （IL-8）介导由ras -突变引起的肿瘤血管生成，ras -突变存在于约90%的胰腺腺癌中。IL-8在胰腺肿瘤中的过度表达被认为可以促进肿瘤血管生成并激活生存信号通路。建立96孔细胞酶联免疫吸附试验（ELISA），筛选Harbor Branch Oceanographic Institute海洋天然产物库中具有抑制BxPC-3胰腺癌细胞产生IL-8能力的天然产物。筛选了一千多个馏分，鉴定出十种已知的具有这种能力的海洋天然产品。这些化合物可分为四类，包括：吡咯亚胺醌类生物碱二巴兹林A和异巴兹林C；mycalamide聚酮类中的mycalamide A和B、onnamide A、discalamide A和操作素K；脂肽microcolin A、环状沉积肽didemin B和去甲didemin B。此外，didemin B、去甲didemin B和theopederin K对四种胰腺癌细胞系具有强的细胞毒性。这些化合物中有许多已被报道抑制蛋白质合成，IL-8产生的减少可能是非特异性的。然而，这是这些化合物的新活性，抑制胰腺癌细胞分泌IL-8的活性现在可以添加到先前报道的dideminins抗血管生成活性中。
Pancreatic cancer presents one of the most negative prognoses of all cancers, as it has usually metastasized by the time a patient is diagnosed. The American Cancer Society estimates that 93% of patients will die within five years of diagnosis, highlighting the need for new drugs to treat this disease. Interleukin 8 (IL-8) mediates the angiogenesis of tumors arising from Ras-mutations which are present in about 90% of pancreatic adenocarcinomas. Overexpression of IL-8 in pancreatic tumors is thought to promote tumor angiogenesis and to activate survival signaling pathways. A 96-well cell-based ELISA assay was set up to screen the Harbor Branch Oceanographic Institute library of marine natural products to identify those with the ability to inhibit IL-8 production by BxPC-3 pancreatic cancer cells. Over a thousand fractions were screened resulting in the identification of ten known marine natural products with this ability. These compounds fall into four classes of compounds including: the pyrroloiminoquinone alkaloids secobatzelline A and isobatzelline C; mycalamide A and B, onnamide A, discalamide A and theopederin K from the mycalamide class of polyketides; the lipopeptide microcolin A, and the cyclic depsipeptides didemnin B and nordidemnin B. In addition, Didemnin B, nordidemnin B and theopederin K induce potent cytotoxicity against four pancreatic cancer cell lines tested. Many of these compounds have been previously reported to inhibit protein synthesis and the decrease in IL-8 production may be non-specific. Nevertheless, this is a new activity for these compounds and inhibition of IL-8 secretion by pancreatic cancer cells can now be added to the previously reported antiangiogenic activities of the didemnins.