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

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• 作者：Thangaiyan Rabi ; Carlo V. Catapano
• 关键词：Aphanin ; Pancreatic cancer ; Apoptosis ; Oncogenic K ; Ras ; STAT3 ; ROS
• 刊名：Tumor Biology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：37
• 期：9
• 页码：12455-12464
• 全文大小：1,290 KB
• 刊物主题：Cancer Research;
• 出版者：Springer Netherlands
• ISSN：1423-0380
• 卷排序：37

文摘

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 1H-NMR, 13C-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 (ΔKRASG12D) 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.