title: Grape Seed Procyanidin Extract Mediates Antineoplastic Effects against Lung Cancer via Modulations of Prostacyclin and 15-HETE Eicosanoid Pathways.
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)/PGI2and 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 PGI2and 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.
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine Section, New Mexico Veterans Administration Health Care System, and University of New Mexico, Albuquerque, New Mexico. Jenny.Mao@va.gov.
authors.forename: Jenny T
authors.initials: JT
authors.lastname: Mao
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine Section, New Mexico Veterans Administration Health Care System, and University of New Mexico, Albuquerque, New Mexico.
authors.forename: Jane
authors.initials: J
authors.lastname: Smoake
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine Section, New Mexico Veterans Administration Health Care System, and University of New Mexico, Albuquerque, New Mexico.
authors.forename: Heesung K
authors.initials: HK
authors.lastname: Park
authors.affiliation: UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Qing-Yi
authors.initials: QY
authors.lastname: Lu
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine Section, New Mexico Veterans Administration Health Care System, and University of New Mexico, Albuquerque, New Mexico.
authors.forename: Bingye
authors.initials: B
authors.lastname: Xue
mesh_terms: D000072283:A549 Cells; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D044946:Biflavonoids / Q000494:pharmacology / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid; D001999:Bronchoscopy; D053148:Caspase 3 / Q000378:metabolism; D002392:Catechin / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015777:Eicosanoids / Q000032:analysis; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D005240:Feasibility Studies; D056604:Grape Seed Extract / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy*; D010865:Pilot Projects; D044945:Proanthocyanidins / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D044946:Biflavonoids; D015777:Eicosanoids; D056604:Grape Seed Extract; D044945:Proanthocyanidins; D034741:RNA, Small Interfering; C000624588:leucoselect phytosome; C017674:procyanidin; D002392:Catechin; D003577:Cytochrome P-450 Enzyme System; C059164:15-hydroxy-5,8,11,13,17-eicosapentaenoic acid; D015118:Eicosapentaenoic Acid; D053148:Caspase 3; D019746:Intramolecular Oxidoreductases; C472456:PTGIS protein, human; C022461:prostacyclin synthetase