TY - JOUR
T1 - Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana
AU - Arai, Midori A.
AU - Tateno, Chikashi
AU - Hosoya, Takahiro
AU - Koyano, Takashi
AU - Kowithayakorn, Thaworn
AU - Ishibashi, Masami
N1 - Funding Information:
We are very grateful to Drs. Fritz Aberger and Gerhard Regl (University of Salzburg) for the kind provision of tetracycline-regulated HaCaT cells. This work was partly supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
PY - 2008/11/1
Y1 - 2008/11/1
N2 - The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. By screening tropical plant extracts by using our screening system, Zizyphus cambodiana was found to include Hh/GLI signaling inhibitors. Bioassay-guided fractionation of this plant extract led to the isolation of three active pentacyclic triterpenes, colubrinic acid (1), betulinic acid (2) and alphitolic acid (3), as potent inhibitors. The inhibition of GLI-related protein expression with 1 or 2 was observed in HaCaT cells with exogenous GLI1, or human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited by 1 or 2. We also examined the cytotoxicity of these active compounds against PANC1, human prostate cancer cells (DU145) and mouse embryo fibroblast cells (C3H10T1/2). The cytotoxicity against cancer cells (PANC1 and DU145) by 1 or 2 would be caused by inhibition of the expression of the anti-apoptosis protein BCL2. These pentacyclic triterpene inhibitors showed an important relationship between Hh/GLI signaling inhibition, the decrease of BCL2, and cytotoxicity against cancer cells.
AB - The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. By screening tropical plant extracts by using our screening system, Zizyphus cambodiana was found to include Hh/GLI signaling inhibitors. Bioassay-guided fractionation of this plant extract led to the isolation of three active pentacyclic triterpenes, colubrinic acid (1), betulinic acid (2) and alphitolic acid (3), as potent inhibitors. The inhibition of GLI-related protein expression with 1 or 2 was observed in HaCaT cells with exogenous GLI1, or human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited by 1 or 2. We also examined the cytotoxicity of these active compounds against PANC1, human prostate cancer cells (DU145) and mouse embryo fibroblast cells (C3H10T1/2). The cytotoxicity against cancer cells (PANC1 and DU145) by 1 or 2 would be caused by inhibition of the expression of the anti-apoptosis protein BCL2. These pentacyclic triterpene inhibitors showed an important relationship between Hh/GLI signaling inhibition, the decrease of BCL2, and cytotoxicity against cancer cells.
KW - Colubrinic acid
KW - GLI
KW - Hedgehog
KW - Zizyphus cambodiana
UR - http://www.scopus.com/inward/record.url?scp=53749085689&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=53749085689&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2008.09.053
DO - 10.1016/j.bmc.2008.09.053
M3 - Article
C2 - 18842418
AN - SCOPUS:53749085689
SN - 0968-0896
VL - 16
SP - 9420
EP - 9424
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 21
ER -
