| Autor: |
Yahagi H; Laboratory of Pharmacognosy and Natural Product Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan., Yahagi T; Laboratory of Pharmacognosy and Natural Product Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan., Matsumura M; Laboratory of Pharmacognosy and Natural Product Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan., Igarashi K; Laboratory of Pharmacognosy and Natural Product Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan., Yokoyama N; Laboratory of Pharmacognosy and Natural Product Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan., Matsuzaki K; Laboratory of Pharmacognosy and Natural Product Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan. matsuzaki.keiichi@nihon-u.ac.jp. |
| Abstrakt: |
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 compounds 1 and 2 were 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 IC 50 values of 18.0 ± 0.6 and 13.3 ± 2.2 µM, respectively. Mechanistically, 2 reduced 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 decreased Glut1 mRNA. These results indicate that 2 inhibits hypoxia signaling through a mechanism involving the reduction of HIF-1α protein levels and Glut1 mRNA and may have anti-pancreatic cancer effects. |
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