title: Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism.
abstract: Cannabinoids (CBs) are implicated in the control of cell survival in different types of tumors, but little is known about the role of CB system in pancreatic cancer. Herein, we investigated the in vitro antitumor activity of CBs and the potential role of their receptors in human pancreatic cancer cells MIA PaCa-2. Characterization tools used for this study included growth inhibition/cell viability analyses, caspase 3/7 induction, DNA fragmentation, microarray analysis and combination index-isobologram method. Our results demonstrate that CBs produce a significant cytotoxic effect via a receptor-independent mechanism. The CB1 antagonist N-(piperidin-1-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) was the most active compound with an IC50 of 8.6 +/- 1.3 microM after 72 h. AM251 induces apoptosis, causes transcriptional changes of genes in janus kinase/signal transducers and activators of transcription signaling network and synergistically interacts with the pyrimidine analogue, 5-fluorouracil. These findings exclude the involvement of CB receptors in the regulation of MIA PaCa-2 cell growth and put AM251 forward as a candidate for the development of novel compounds worthy to be tested in this type of neoplasia.
authors.affiliation: Department of Psychiatry, University of Pisa, Via Bonanno, 6, 56126 Pisa, PI, Italy. s.fogli@med.unipi.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Fogli
authors.forename: Paola
authors.initials: P
authors.lastname: Nieri
authors.forename: Andrea
authors.initials: A
authors.lastname: Chicca
authors.forename: Barbara
authors.initials: B
authors.lastname: Adinolfi
authors.forename: Veronica
authors.initials: V
authors.lastname: Mariotti
authors.forename: Paola
authors.initials: P
authors.lastname: Iacopetti
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Breschi
authors.forename: Silvia
authors.initials: S
authors.lastname: Pellegrini
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid
chemical_list: D000970:Antineoplastic Agents; D002186:Cannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C103505:AM 251