Aphanin, a triterpenoid from Amoora rohituka inhibits K-Ras mutant activity and STAT3 in pancreatic carcinoma cells.

Details

Serval ID
serval:BIB_CDA68D029121
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Aphanin, a triterpenoid from Amoora rohituka inhibits K-Ras mutant activity and STAT3 in pancreatic carcinoma cells.
Journal
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
Author(s)
Rabi T., Catapano C.V.
ISSN
1423-0380 (Electronic)
ISSN-L
1010-4283
Publication state
Published
Issued date
09/2016
Peer-reviewed
Oui
Volume
37
Number
9
Pages
12455-12464
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Mutations of the K-Ras gene occur in over 90 % of pancreatic carcinomas, and to date, no targeted therapies exist for this genetically defined subset of cancers. STAT3 plays a critical role in KRAS-driven pancreatic tumorigenesis, suggesting its potential as a therapeutic target in this cancer. Therefore, finding novel and potential drugs to inhibit oncogenic K-Ras is a major challenge in cancer therapy. In an attempt to develop novel anti-KRAS mutant chemotherapeutics, we isolated three novel triterpenoids from Amoora rohituka stem and their chemical structures were characterized by extensive (1)H-NMR, (13)C-NMR, Mass, IR spectroscopic studies and chemical transformations. Aphanin (3 alpha-angeloyloxyolean-12-en-28-oic acid) is one of the isolated novel triterpenoid compounds. We found aphanin exhibited antiproliferative effects, caused G0-G1 cell cycle arrest, inhibits K-Ras G12D mutant activity by decreased STAT3, p-STAT3, Akt, p-Akt, cyclin D1 and c-Myc expressions, and induced apoptosis in pancreatic cancer HPAF-II (ΔKRAS (G12D) ) cells. The apoptosis proceeded through depletion of GSH with a concomitant increase in the reactive oxygen species production. The results of our study have important implications for the development of aphanin as potential novel agent for the treatment of K-Ras mutant pancreatic cancer, and STAT3-cMyc-cyclinD1 axis may serve as an important predictive biomarker for the therapeutic efficacy.

Keywords
Cell Line, Tumor, Cell Proliferation/drug effects, Glutathione/metabolism, Humans, Meliaceae/chemistry, Mutation, Pancreatic Neoplasms/drug therapy, Pancreatic Neoplasms/genetics, Phosphorylation, Proto-Oncogene Proteins c-akt/antagonists & inhibitors, Proto-Oncogene Proteins c-myc/antagonists & inhibitors, Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors, Proto-Oncogene Proteins p21(ras)/genetics, STAT3 Transcription Factor/physiology, Triterpenes/pharmacology
Pubmed
Create date
01/07/2016 10:05
Last modification date
20/08/2019 15:48
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