Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana.
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.
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
Midori A
MA
Arai
Chikashi
C
Tateno
Takahiro
T
Hosoya
Takashi
T
Koyano
Thaworn
T
Kowithayakorn
Masami
M
Ishibashi
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D008297:Male; D008453:Maytansine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D053978:Pentacyclic Triterpenes; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1; D016335:Zinc Fingers; D031957:Ziziphus / Q000737:chemistry*; D000094062:Betulinic Acid
D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D053978:Pentacyclic Triterpenes; D010636:Phenols; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014315:Triterpenes; D000071676:Zinc Finger Protein GLI1; C113440:alphitol; D008453:Maytansine; C013448:colubrinol; D010626:Phenylethyl Alcohol; D000094062:Betulinic Acid