Inhibitory activity of flavonoids from Ephedrae Herba on hypoxia signaling in PANC-1 cells and the evaluation of their mechanisms
Inhibitory activity of flavonoids from Ephedrae Herba on hypoxia signaling in PANC-1 cells and the evaluation of their mechanisms
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麻黄黄酮对 PANC-1 细胞缺氧信号的抑制活性及其机制评价
DOI：
10.1007/s11418-021-01507-z
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发表时间：
2021
影响因子：
3.3
通讯作者：
Matsuzaki Keiichi
中科院分区：
文献类型：
--
作者：
Yahagi Hiroaki;Yahagi Tadahiro;Matsumura Miki;Igarashi Kota;Yokoyama Natsumi;Matsuzaki Keiichi
胰腺癌是一种预后极差的致命疾病。近年来的研究表明，缺氧诱导因子（HIF）介导的缺氧信号通路参与了胰腺癌的发生发展。因此，阐明缺氧信号传导抑制剂可能会导致新的抗癌药物的候选人的发展。在我们从生药提取物中筛选HIF抑制剂的过程中，从麻黄的丙酮提取物中分离出新的酰化山奈酚糖苷，山奈酚3-O-[4″-（E）-p-香豆酰基-3 ″-O-二羟基棕榈基]鼠李糖苷（1）和山奈酚3-O-[4″-（E）-p-香豆酰基-2 ″-O-二羟基棕榈基]鼠李糖苷（2），以及八种已知的黄酮醇糖苷（3-10）。通过光谱和化学分析确定了新化合物1和2的结构。在PANC-1胰腺癌细胞系中使用基于细胞的HRE驱动的荧光素酶报告基因测定，我们发现这些化合物对缺氧信号传导表现出有效的抑制活性，IC 50值分别为18.0 ± 0.6和13.3 ± 2.2 µM。从机制上讲，2在30 µM时通过泛素-蛋白酶体途径减少了细胞核中HIF-1α蛋白的量，而对HIF蛋白从细胞质中的核转位没有影响，随后减少了Glut 1 mRNA。这些结果表明2通过降低HIF-1α蛋白水平和Glut 1 mRNA水平抑制缺氧信号传导，可能具有抗胰腺癌作用。
Pancreatic cancer is a lethal disease with a very poor prognosis. Recent reports indicate that hypoxia signaling mediated by hypoxia-inducible factor (HIF) contributes to the progression of pancreatic cancer. Therefore, elucidating the inhibitor of hypoxia signaling may lead to the development of a candidate for new anticancer agents. During our screening program for HIF inhibitor from crude drug extracts, new acylated kaempferol glycosides, kaempferol 3-O-[4″-(E)-p-coumaroyl-3″-O-dihydroxypalmityl] rhamnoside (1) and kaempferol 3-O-[4″-(E)-p-coumaroyl-2″-O-dihydroxypalmityl] rhamnoside (2), were isolated from an acetone extract of Ephedrae Herba, together with eight known flavonol glycosides (3–10). The structures of novel compounds1and2were elucidated based on spectroscopic and chemical analyses. Using a cell-based HRE-driven luciferase reporter assay in a PANC-1 pancreatic cancer cell line, we found that these compounds demonstrated potent inhibitory activity on hypoxia signaling with IC50values of 18.0 ± 0.6 and 13.3 ± 2.2 µM, respectively. Mechanistically,2reduced the amount of HIF-1α protein in the nuclear at 30 µM via the ubiquitin–proteasome pathway with no effect on the nuclear translocation of HIF proteins from cytosol and subsequently decreasedGlut1mRNA. These results indicate that2inhibits hypoxia signaling through a mechanism involving the reduction of HIF-1α protein levels andGlut1mRNA and may have anti-pancreatic cancer effects.
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作者：
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DOI：
--
发表时间：
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期刊：
Bioscience, biotechnology and biochemistry
影响因子：
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