title: Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis.
abstract: Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E2(PGE2) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE2biosynthesis. We show that low-dose aspirin inhibits systemic PGE2biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE2biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE2production by the platelet-tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE2biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855-65. ©2016 AACR.
authors.affiliation: Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee. olivier.boutaud@vanderbilt.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boutaud
authors.affiliation: Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.|Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: I Romina
authors.initials: IR
authors.lastname: Sosa
authors.affiliation: Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Taneem
authors.initials: T
authors.lastname: Amin
authors.affiliation: Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Denise
authors.initials: D
authors.lastname: Oram
authors.affiliation: Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: David
authors.initials: D
authors.lastname: Adler
authors.affiliation: Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Hyun S
authors.initials: HS
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Crews
authors.affiliation: Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Ginger
authors.initials: G
authors.lastname: Milne
authors.affiliation: Department of Cancer Biology; and the Thoracic Program, Vanderbilt Ingram Cancer Center, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Bradford K
authors.initials: BK
authors.lastname: Harris
authors.affiliation: Department of Cancer Biology; and the Thoracic Program, Vanderbilt Ingram Cancer Center, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Megan
authors.initials: M
authors.lastname: Hoeksema
authors.affiliation: Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Bjorn C
authors.initials: BC
authors.lastname: Knollmann
authors.affiliation: Department of Cancer Biology; and the Thoracic Program, Vanderbilt Ingram Cancer Center, School of Medicine, Vanderbilt University, Nashville, Tennessee.|Department of Medicine, Meharry Medical College, Nashville, Tennessee.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Lammers
authors.affiliation: Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.affiliation: Department of Cancer Biology; and the Thoracic Program, Vanderbilt Ingram Cancer Center, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
authors.affiliation: Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee.|Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: John A
authors.initials: JA
authors.lastname: Oates
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D001241:Aspirin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D001241:Aspirin