title: Therapeutic potential of sulindac hydroxamic acid against human pancreatic and colonic cancer cells.
abstract: The non-steroidal anti-inflammatory drug (NSAID) sulindac exhibits cyclooxygenase (COX)-dependent and COX-independent chemopreventive properties in human cancer. The present study was aimed at investigating whether the hydroxamic acid substitution for the carboxylic acid group could enhance the in vitro antitumor and antiangiogenic activities of sulindac. Characterization tools used on this study included analyses of cell viability, caspase 3/7 induction, DNA fragmentation, and gene expression. Our findings demonstrate that the newly synthesized hydroxamic acid derivative of sulindac and its sulfone and sulfide metabolites were characterized by a good anticancer activity on human pancreatic and colon cancer cells, both in terms of potency (IC(50) mean values from 6 ± 1.1 μM to 64 ± 1.1 μM) and efficacy (E(max) of ∼100%). Hydroxamic acid derivatives trigger a higher degree of apoptosis than carboxylic acid counterparts, increase bax/bcl-2 expression ratio and induce caspase 3/7 activation. Most notably, these compounds significantly inhibit proangiogenic growth factor-stimulated proliferation of vascular endothelial cell (HUVEC) at sub-micromolar concentrations. Our data also provide evidence that the COX-active metabolite of sulindac hydroxamic acid were the most active of the series and selective inhibition of COX-1 but not COX-2 can mimic its effects, suggesting that COX inhibition could only play a partial role in the mechanism of compound action. In conclusion, these data demonstrate that substitution of the carboxylic acid group with the hydroxamic acid moiety enhances in vitro antiproliferative, proapoptotic and antiangiogenic properties of sulindac, therefore increasing the therapeutic potential of this drug.
authors.affiliation: Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy. s.fogli@farm.unipi.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Fogli
authors.forename: Irene
authors.initials: I
authors.lastname: Banti
authors.forename: Fabio
authors.initials: F
authors.lastname: Stefanelli
authors.forename: Luca
authors.initials: L
authors.lastname: Picchianti
authors.forename: Maria
authors.initials: M
authors.lastname: Digiacomo
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Breschi
authors.forename: Annalina
authors.initials: A
authors.lastname: Lapucci
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010190:Pancreatic Neoplasms / Q000473:pathology*; D013467:Sulindac / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D013467:Sulindac; D053148:Caspase 3; D053179:Caspase 7