title: Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses.The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients.
authors: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Arnau
authors: A
authors: Montraveta
authors: Sílvia
authors: S
authors: Xargay-Torrent
authors: Mónica
authors: M
authors: López-Guerra
authors: Laia
authors: L
authors: Rosich
authors: Patricia
authors: P
authors: Pérez-Galán
authors: Itziar
authors: I
authors: Salaverria
authors: Silvia
authors: S
authors: Beà
authors: Susana G
authors: SG
authors: Kalko
authors: Mercè
authors: M
authors: de Frias
authors: Clara
authors: C
authors: Campàs
authors: Gaël
authors: G
authors: Roué
authors: Dolors
authors: D
authors: Colomer
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D011897:Random Allocation; D012263:Ribonucleosides / Q000008:administration & dosage / Q000494:pharmacology*; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; D000069283:Rituximab; C011651:acadesine