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
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Arnau Montraveta1, Sílvia Xargay-Torrent1, Mónica López-Guerra1, Laia Rosich1, Patricia Pérez-Galán1, Itziar Salaverria1, Silvia Beà1, Susana G. Kalko2, Mercè de Frias3, Clara Campàs3, Gaël Roué1, Dolors Colomer1,4
1 Experimental Therapeutics in Lymphoid Malignancies Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain,
2 Bioinformatics Core Facility, IDIBAPS, Barcelona, Spain
3 Advancell-Advanced In Vitro Cell Technologies S.A., Barcelona, Spain
4 Hematopathology Unit, Hospital Clínic, Barcelona, Spain
Dolors Colomer, email:
Gaël Roué, email:
Keywords: Acadesine, rituximab mantle cell lymphoma, xenograft mouse model
Received: September 30, 2013 Accepted: January 23, 2014 Published: January 25, 2014
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.
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