title: 2-Methoxy-5-amino-N-hydroxybenzamide, a derivative of mesalamine, inhibits colon cancer cell growth through cyclo-oxygenase-2-dependent and -independent mechanisms.
abstract: COX-2 (cyclo-oxygenase-2) and PGE₂ (prostaglandin E₂) play a key role in sustaining CRC (colorectal cancer) cell growth and survival. Indeed, the use of agents targeting the COX-2/PGE₂ axis has been associated with a reduction in the development of CRC in both humans and murine models of colon carcinogenesis. In the present study, we investigated whether 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a derivative of mesalamine that inhibits CRC cell growth both in vitro and in vivo, negatively regulates COX-2/PGE₂ expression in CRC cells and assessed whether the 2-14-mediated anti-neoplastic effect is strictly dependent on the inhibition of this pathway. Our results show that 2-14 blocks the growth and enhances the death of HT-115, a CRC cell line overexpressing COX-2, and that these effects associate with inhibition of COX-2 but not COX-1. 2-14 also down-regulates TNFα (tumour necrosis factor α)-induced COX-2 in HT-29 cells as well as COX-2/PGE₂ expression in ex vivo cultures of human CRC explants. Similarly, 2-14 reduces COX-2, but not COX-1, in tumoural areas developing in a mouse model of CAC (colitis-associated colon cancer). Finally, we show that 2-14 exhibits in vitro and in vivo anti-mitogenic effects in DLD-1, a COX-deficient CRC cell line. Taken together, these results suggest that 2-14 inhibits CRC cell growth through COX-2-dependent and -independent mechanisms.
authors.affiliation: Department of Internal Medicine, University of Rome 'Tor Vergata', Rome, Italy. Carmine.stolfi@uniroma2.it
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Franzè
authors.forename: Ivan
authors.initials: I
authors.lastname: Monteleone
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.forename: Luana
authors.initials: L
authors.lastname: Franceschilli
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Sileri
authors.forename: Giuseppe S
authors.initials: GS
authors.lastname: Sica
authors.forename: Achille L
authors.initials: AL
authors.lastname: Gaspari
authors.forename: Giovanna
authors.initials: G
authors.lastname: Del Vecchio Blanco
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000636:Aminosalicylic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C547423:2-methoxy-5-amino-N-hydroxybenzamide; D000636:Aminosalicylic Acids; D000970:Antineoplastic Agents; D015415:Biomarkers; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone