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

Hifzur Rahman Siddique, D. Joshua Liao, Shrawan Kumar Mishra, Todd Schuster, Lei Wang, Brock Matter, Paul M. Campbell, Peter Villalta, Sanjeev Nanda, Yibin Deng, Mohammad Saleem

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1720-1731
Number of pages12
JournalInternational Journal of Cancer
Volume131
Issue number7
DOIs
StatePublished - Oct 1 2012

Fingerprint

Pancreatic Ductal Carcinoma
Catechin
Polyphenols
Growth
Adenocarcinoma
Epithelial Cells
NF-kappa B
Tandem Mass Spectrometry
Liquid Chromatography
ras Proteins
Neoplasms
In Vitro Techniques
Guanosine Triphosphate
Tumor Cell Line
Heterografts
Oral Administration
Phosphorylation
Clinical Trials
Pharmacology
Food

Keywords

  • cocoa polyphenol
  • epicatechin
  • Kras
  • pancreatic cancer
  • preneoplastic

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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

In: International Journal of Cancer, Vol. 131, No. 7, 01.10.2012, p. 1720-1731.

Research output: Contribution to journalArticle

Siddique, HR, Liao, DJ, Mishra, SK, Schuster, T, Wang, L, Matter, B, Campbell, PM, Villalta, P, Nanda, S, Deng, Y & Saleem, M 2012, 'Epicatechin-rich cocoa polyphenol inhibits Kras-activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model', International Journal of Cancer, vol. 131, no. 7, pp. 1720-1731. https://doi.org/10.1002/ijc.27409
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. / Epicatechin-rich cocoa polyphenol inhibits Kras-activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model. In: International Journal of Cancer. 2012 ; Vol. 131, No. 7. pp. 1720-1731.
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abstract = "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.",
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AU - Wang, Lei

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AU - Campbell, Paul M.

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