Grape Seed Procyanidin Extract Mediates Antineoplastic Effects against Lung Cancer via Modulations of Prostacyclin and 15-HETE Eicosanoid Pathways

Cancer Prev Res (Phila). 2016 Dec;9(12):925-932. doi: 10.1158/1940-6207.CAPR-16-0122. Epub 2016 Sep 22.

Abstract

Grape seed procyanidin extract (GSE) has been reported to exert antineoplastic properties via the inhibition of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) eicosanoid pathways. In addition, ample data link carcinogenesis to inflammatory events involving other major eicosanoid metabolic pathways, including prostacyclin (PGI2) and 15-hydroxyeicosatetraenoic acid (15-HETE). We therefore evaluated the effects of GSE on prostacyclin synthase (PTGIS)/PGI2 and 15-lipoxigenase-2 (15-LOX-2)/15-HETE productions by human lung premalignant and malignant cells and correlated the findings with antiproliferative or proapoptotic effects of GSE. The effects of GSE on PGI2 and 15-HETE productions by human bronchoalveolar lavage (BAL) cells ex vivo were also determined. We further evaluated the bioactivity of oral administration of leucoselect phytosome (a standardized GSE) in the lungs of subjects participating in a lung cancer chemoprevention trial, by comparing the antiproliferative effects of coculturing matched pre- versus posttreatment BAL fluids with lung premalignant and malignant cells. GSE significantly increased PGI2 (as measured by 6-keto PGF1α) and 15-HETE productions by these cells. Transfections of PTGIS or 15-LOX-2-specific siRNA partially abrogated the antiproliferative or proapoptotic effects of GSE in lung premalignant and malignant cells, respectively. GSE also increased PTGIS and inhibition of caspase-3, and transfection of 15-LOX-2 siRNA abrogated the GSE-induced apoptosis in A549 cells. In addition, culture supernatants from ex vivo GSE-treated baseline BAL cells, as well as BAL fluids from subjects treated with leucoselect phytosome, significantly decreased proliferations of lung premalignant and malignant cells. Our findings support the continued investigation of GSE as an anti-neoplastic and chemopreventive agent against lung cancer. Cancer Prev Res; 9(12); 925-32. ©2016 AACR.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • A549 Cells
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Apoptosis / drug effects
  • Biflavonoids / pharmacology
  • Biflavonoids / therapeutic use
  • Bronchoalveolar Lavage Fluid
  • Bronchoscopy
  • Caspase 3 / metabolism
  • Catechin / pharmacology
  • Catechin / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Coculture Techniques
  • Cytochrome P-450 Enzyme System / metabolism*
  • Eicosanoids / analysis
  • Eicosapentaenoic Acid / analogs & derivatives*
  • Eicosapentaenoic Acid / metabolism
  • Feasibility Studies
  • Grape Seed Extract / pharmacology
  • Grape Seed Extract / therapeutic use*
  • Humans
  • Intramolecular Oxidoreductases / metabolism*
  • Lung Neoplasms / drug therapy*
  • Pilot Projects
  • Proanthocyanidins / pharmacology
  • Proanthocyanidins / therapeutic use
  • RNA, Small Interfering / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Antioxidants
  • Biflavonoids
  • Eicosanoids
  • Grape Seed Extract
  • Proanthocyanidins
  • RNA, Small Interfering
  • leucoselect phytosome
  • procyanidin
  • Catechin
  • Cytochrome P-450 Enzyme System
  • 15-hydroxy-5,8,11,13,17-eicosapentaenoic acid
  • Eicosapentaenoic Acid
  • Caspase 3
  • Intramolecular Oxidoreductases
  • PTGIS protein, human
  • prostacyclin synthetase