title: Unlocking Aspirin's Chemopreventive Activity: Role of Irreversibly Inhibiting Platelet Cyclooxygenase-1.
abstract: The mechanism by which aspirin consumption is linked to significant reductions in the incidence of multiple forms of cancer and metastatic spread to distant tissues, resulting in increased cancer patient survival is not well understood. In this study, using colon cancer as an example, we provide both in vitro (cell culture) and in vivo (chemically induced mouse model of colon cancer) evidence that this profound antineoplastic action may be associated with aspirin's ability to irreversibly inhibit COX-1-mediated platelet activation, thereby blocking platelet-cancer cell interactions, which promote cancer cell number and invasive potential. This process may be driven by platelet-induced epithelial-mesenchymal transition (EMT), as assessed using confocal microscopy, based upon changes in cell morphology, growth characteristics and fibronectin expression, and biochemical/molecular analysis by measuring changes in the expression of the EMT markers; vimentin, β-catenin, and SNAIL. We also provide evidence that a novel, gastrointestinal-safe phosphatidylcholine (PC)-associated aspirin, PL2200 Aspirin, possesses the same or more pronounced actions versus unmodified aspirin with regard to antiplatelet effects (in vitro: reducing platelet activation as determined by measuring the release of thromboxane and VEGF in culture medium; in vivo: inhibiting platelet number/activation and extravasation into tumor tissue) and chemoprevention (in vitro: inhibiting colonic cell growth and invasive activity; in vivo: inhibiting colonic dysplasia, inflammation, and tumor mass). These results suggest that aspirin's chemopreventive effects may be due, in part, to the drug blocking the proneoplastic action of platelets, and the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers. Cancer Prev Res; 10(2); 142-52. ©2016 AACR.
authors.affiliation: Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas. lenard.m.lichtenberger@uth.tmc.edu.
authors.forename: Lenard M
authors.initials: LM
authors.lastname: Lichtenberger
authors.affiliation: Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas.
authors.forename: Dexing
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Bick
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Poindexter
authors.affiliation: Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas.
authors.forename: Tri
authors.initials: T
authors.lastname: Phan
authors.affiliation: Department of Medicine, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Bergeron
authors.affiliation: Department of Medicine, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.
authors.forename: Subhashree
authors.initials: S
authors.lastname: Pradhan
authors.affiliation: Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Dial
authors.affiliation: Department of Medicine, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.
authors.forename: K Vinod
authors.initials: KV
authors.lastname: Vijayan
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015539:Platelet Activation / Q000187:drug effects*
chemical_list: D016861:Cyclooxygenase Inhibitors; D051545:Cyclooxygenase 1; D001241:Aspirin