TY - JOUR
T1 - New hedgehog/GLI-signaling inhibitors from Adenium obesum
AU - Arai, Midori A.
AU - Tateno, Chikashi
AU - Koyano, Takashi
AU - Kowithayakorn, Thaworn
AU - Kawabe, Seiichiro
AU - Ishibashi, Masami
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/2/21
Y1 - 2011/2/21
N2 - The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. We recently constructed a cell-based screening system to search for Hh/GLI signaling inhibitors from natural resources. Using our screening system, Adenium obesum was found to include Hh/GLI signaling inhibitors from our tropical plant extract libraries. Bioassay-guided fractionation of this plant extract led to the isolation of 17 cardiac glycosides (1-17), including 3 new compounds (4, 9, 16). These compounds showed strong inhibitory activities, especially the IC50 of 17 is 0.11 μM. The inhibition of GLI-related protein expression with 3, 9, 11, 15 and 17 was observed in human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited. These compounds also showed selective cytotoxicity against two cancer cell lines, with less effect against normal cells (C3H10T1/2). RT-PCT examinations showed that Ptch mRNA expression by 3, 11, 15 and 17 was inhibited.
AB - The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. We recently constructed a cell-based screening system to search for Hh/GLI signaling inhibitors from natural resources. Using our screening system, Adenium obesum was found to include Hh/GLI signaling inhibitors from our tropical plant extract libraries. Bioassay-guided fractionation of this plant extract led to the isolation of 17 cardiac glycosides (1-17), including 3 new compounds (4, 9, 16). These compounds showed strong inhibitory activities, especially the IC50 of 17 is 0.11 μM. The inhibition of GLI-related protein expression with 3, 9, 11, 15 and 17 was observed in human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited. These compounds also showed selective cytotoxicity against two cancer cell lines, with less effect against normal cells (C3H10T1/2). RT-PCT examinations showed that Ptch mRNA expression by 3, 11, 15 and 17 was inhibited.
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U2 - 10.1039/c0ob00677g
DO - 10.1039/c0ob00677g
M3 - Article
C2 - 21170436
AN - SCOPUS:79551661875
VL - 9
SP - 1133
EP - 1139
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
SN - 1477-0520
IS - 4
ER -