Abstract A209: The nucleoside analogue acadesine exerts antitumoral activity and cooperates with anti-CD20 monoclonal antibodies in in vitro and in vivo models of mantle cell lymphoma.
Authors: Montraveta Arnau , de Frias Merce , Campas Clara , Campo Elias , Roue Gael , Colomer Dolors 
Published: June 2012

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by the t(11;14)(q13:q32) that involves cyclin D1 overexpression and consequent cell cycle deregulation at the G1 phase. This entity is generally characterized by an aggressive course and a bad prognosis. Recently, a specific subtype of MCL has been described, showing best outcomes and that might be managed more conservatively than conventional MCL. These cases are characterized by non-nodal presentation, predominantly hypermutated IgVH, lack of genomic complexity, and absence of SOX11 expression. Acadesine is a nucleoside analogue initially developed as a cardioprotective agent, and which has shown a wide range of metabolic effects, including the activation of AMP-activated protein kinase (AMPK). Acadesine was shown to induce apoptosis in primary cells from several B lymphoid neoplasms and has been entered in a phase I/II clinical trial with relapsed/refractory chronic lymphocytic leukemia (CLL) patients. This clinical study has shown that acadesine plasmatic levels in the micro molar range are achievable and safe when CLL patients are treated with the drug. To evaluate the antitumoral properties of acadesine in MCL, we exposed a set of 11 MCL primary cultures and 9 MCL cell lines for up to 48h with increasing doses of the drug. Cytotoxicity and cytostatic effects were then assessed by flow cytometry detection of annexinV/propidium iodide labeling and MTT proliferation assay, respectively. In both MCL cell lines and MCL primary cultures, we observed a heterogeneous response to the drug, with no correlation to common genetic alterations such as deletion/mutation of P53, ATM or P16 genes. Rec-1, Jeko-1, UPN-1 and JVM-2 were the more sensitive cell lines, with a mean lethal dose 50 (LD50 of 1.57 mM at 24 h and 0.95 mM) at 48h, while 2 cell lines (HBL-2 and Granta-519) showed resistance to the compound (LD50 &gt; 50 mM). Among MCL primary cultures, acadesine showed selective cytotoxic activity against malignant B cells while sparing accompanying T cells at pharmacologically achievable doses. Of note, those cases corresponding to the indolent MCL group showed increased sensitivity to the drug at 24h of treatment, when compared to conventional MCL cases (p=0.03). We observed that acadesine efficiently activates the intrinsic apoptotic pathway in MCL cells by reducing Mcl-1 levels, leading to conformational activation of Bax and Bak, mitochondrial depolarization, generation of reactive oxygen species and caspases processing. In drug combination assays, acadesine showed a synergistic effect when combined with the CD20 monoclonal antibody Rituximab. Finally, SCID mice were subcutaneously inoculated with 107 Jeko-1 cells. At day 12 post-inoculation, mice were randomized and administered for 18 days with either 400 mg/kg acadesine 5 days weekly, Rituximab 10mg/kg weekly, both drugs or vehicle. The combination was significantly more effective than Rituximab or Acadesine monotherapy (P &lt; 0.01). In summary, these results suggest that acadesine exerts significant antitumoral activity in both in vitro and in vivo model of MCL, while its combination with CD20 monoclonal antibodies may represent a new therapeutic approach for this entity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A209.