AICAR Induces Apoptosis In B Lymphocytes From Balb/c Mice and Its Effect In Chronic Lymphocytic Leukemia Cells Is Synergic or Additive with Current Chemotherapy
Authors: González-Gironès Diana M , Santidrián Antonio F , Iglesias-Serret Daniel , Cosialls Ana M , Pérez-Perarnau Alba , Rubio-Patiño Camila , de Frias Mercè , de Sevilla Alberto Fernandez , González-Barca Eva , de la Banda Esmeralda , Pons Gabriel , Campàs Clara , Gil Joan 
Published: October 2019

Abstract 1815

AICAR (5-aminoimidazole-4-carboxamide riboside or acadesine) induces apoptosis in chronic lymphocytic leukemia (CLL) cells, without affecting primary T lymphocytes (Campàs et al, Bood 2003). Available treatments for this disease generally induce remission, although nearly all patients relapse and CLL remains incurable. Thus, AICAR is a promising drug for the treatment of this B-cell neoplasm. It has been recently published that AICAR induces apoptosis by a p53- and AMPK-independent mechanism through upregulation of BIM and NOXA in CLL cells (Santidrián&González-Gironès et al, Blood in press). A clinical phase I/II study of AICAR is currently being conducted in CLL patients (http://clinicaltrials.gov/ct2/NCT00559624 ). This clinical study has shown that AICAR plasmatic levels in the micro molar range are achievable and safe when CLL patients are treated with the drug. In vivo assays were performed in mice to analyze the effects of AICAR on the peripheral lymphocyte population. Thus, 0.5 mg/g AICAR was administered intraperitoneally to Balb/c mice every 12 hours and every day blood was collected from the tail of treated (n = 3) and untreated (n = 3) mice. Significant differences (p< .05) were observed between control and treated groups in the number of lymphocytes from day 3 to 6 while the number of total leucocytes did not change. From day 4 the peripheral lymphocyte population started to recover and mice were sacrificed at day 8. In addition, AICAR induced a significant reduction (p< .05) on the percentage of B cells from day 3 to 5. Therefore, AICAR is effective in vivo decreasing the number of peripheral B lymphocytes. From the therapeutic point of view, it is interesting to analyze whether AICAR could synergize with the cytotoxic activity of the current chemotherapy used in CLL patients. Thus, cells from CLL patients (n = 4) were treated with AICAR (0.125, 0.25, 0.5 and 1 mM) and/or dexamethasone (1, 2.5, 5 and 10 μM), fludarabine (0.3, 0.6, 1.5 and 3 μM), chlorambucil (1.25, 2.5, 5 and 10 μM), mafosfamide (the active metabolite of cyclophosphamide) (0.25, 0.5, 1 and 2 μg/mL), rituximab (10, 25, 50 and 100 μg/mL) or alemtuzumab (1.25, 2.5, 5 and 10 μg/mL). The cytotoxic effect of the alkylating agents chlorambucil and mafosfamide was synergic or additive with the effect of AICAR in CLL cells depending on the concentration used of both drugs. The glucocorticoid dexamethasone synergized with AICAR in half of the samples analyzed. As for the nucleoside analogue fludarabine and the monoclonal antibodies rituximab and alemtuzumab, their apoptotic effect was additive with AICAR at some concentrations. Together, AICAR induces apoptosis in B lymphocytes from Balb/c mice when administered intraperitoneally and its cytotoxic effect in CLL cells is synergic or additive with the most common chemotherapy used in CLL treatment.

Disclosures:

de Frias: Advancell: Employment. Campàs:Advancell: Employment.