Abstract
Background: Chronic Lymphocytic Leukemia (CLL) is the most frequent form of leukemia in adult population (22−30% of all leukemia cases). A significant percentage of cases (up to 37%) does not respond to chemotherapeutic treatment or become resistant (up to 76%). Cell death evasion and progressive accumulation of B-cells are the most relevant events in CLL pathogenesis; therefore, targeting apoptotic pathways has been suggested as novel therapeutic approaches. One drawback of this therapeutic strategy is the resistance to death receptor (DR) induced cell death in CLL patients. Here, we investigated the ability of quercetin, a natural flavonoid, to sensitize primary cells from CLL patients to apoptosis triggered by anti-CD95 and recombinant TRAIL (rTRAIL). Material and Methods: Mononucler cells were isolated from peripheral blood of 29 patients affected by CLL. All clinical samples were obtained with written informed consent. Cell viability was measured after 24−48 h stimulation with quercetin, rTRAIL and anti-CD95. Markers of DR-induced apoptosis were assayed, such as caspase-3 and -9 activation, Annexin V positivity, PARP degradation. Results: Quercetin significantly potentiated sensitivity to anti-CD95 and rTRAIL treatment with an increase in cell death of about 10and 17-fold respectively compared to DR mono-treatments. Cell death was due to apoptosis because reduced cell viability paralleled with increased caspase-3 and -9, degradation of PARP, and increased percentage of cells positive to Annexin V. Conclusions: We demonstrate that quercetin is able to enhance apoptosis in cells isolated from CLL patients when associated to rTRAIL or anti-CD95. Overall, the present work demonstrates that resistance to DR-mediated cell death in leukemic cells can be ameliorated or bypassed by the addition of quercetin. In our view, this represents an important issue which stimulates further studies in the direction of therapeutic use of the molecule.
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