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Tumour Biol. 2016 Sep;37(9):12455-12464. Epub 2016 Jun 22.

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

Author information

1
Siddha Clinic and Research Center SVA, Kanyakumari, Tamil Nadu, India. thangaiyanrabi@hotmail.com.
2
Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland. thangaiyanrabi@hotmail.com.
3
Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
4
Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

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 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 (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:

Aphanin; Apoptosis; Oncogenic K-Ras; Pancreatic cancer; ROS; STAT3

PMID:
27333990
DOI:
10.1007/s13277-016-5102-2
[Indexed for MEDLINE]

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