Epicatechin-rich cocoa polyphenol inhibits Kras-activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model

• Published in: International journal of cancer 2012-10, Vol.131 (7), p.1720-1731
• Main Authors: Siddique, Hifzur Rahman, Liao, D. Joshua, Mishra, Shrawan Kumar, Schuster, Todd, Wang, Lei, Matter, Brock, Campbell, Paul M., Villalta, Peter, Nanda, Sanjeev, Deng, Yibin, Saleem, Mohammad
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cacao - chemistry; Cancer; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Catechin - chemistry; Cell Cycle Checkpoints - drug effects; Cell Proliferation; Cell Transformation, Neoplastic - drug effects; Cocoa; cocoa polyphenol; Disease Models, Animal; epicatechin; Gastroenterology. Liver. Pancreas. Abdomen; Genes, ras; Humans; Kras; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical research; Medical sciences; Mice; Mice, Nude; NF-kappa B - genetics; NF-kappa B - metabolism; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation - drug effects; Polyphenols; Polyphenols - administration & dosage; Polyphenols - pharmacology; preneoplastic; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Rodents; Tandem Mass Spectrometry; Transcription, Genetic; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27409

Activated Kras gene coupled with activation of Akt and nuclear factor‐kappa B (NF‐κB) triggers the development of pancreatic intraepithelial neoplasia, the precursor lesion for pancreatic ductal adenocarcinoma (PDAC) in humans. Therefore, intervention at premalignant stage of disease is considered as an ideal strategy to delay the tumor development. Pancreatic malignant tumor cell lines are widely used; however, there are not relevant cell‐based models representing premalignant stages of PDAC to test intervention agents. By employing a novel Kras‐driven cell‐based model representing premalignant and malignant stages of PDAC, we investigated the efficacy of ACTICOA‐grade cocoa polyphenol (CP) as a potent chemopreventive agent under in vitro and in vivo conditions. It is noteworthy that several human intervention/clinical trials have successfully established the pharmacological benefits of cocoa‐based foods. The liquid chromatography (LC)–mass spectrometry (MS)/MS data confirmed epicatechin as the major polyphenol of CP. Normal, nontumorigenic and tumorigenic pancreatic ductal epithelial (PDE) cells (exhibiting varying Kras activity) were treated with CP and epicatechin. CP and epicatechin treatments induced no effect on normal PDE cells, however, caused a decrease in the (i) proliferation, (ii) guanosine triphosphate (GTP)‐bound Ras protein, (iii) Akt phosphorylation and (iv) NF‐κB transcriptional activity of premalignant and malignant Kras‐activated PDE cells. Further, oral administration of CP (25 mg/kg) inhibited the growth of Kras‐PDE cell‐originated tumors in a xenograft mouse model. LC–MS/MS analysis of the blood showed epicatechin to be bioavailable to mice after CP consumption. We suggest that (i) Kras‐driven cell‐based model is an excellent model for testing intervention agents and (ii) CP is a promising chemopreventive agent for inhibiting PDAC development.