Abstract
B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL.
Highlights
B cell chronic lymphocytic leukemia is characterized by a progressive accumulation of monoclonal mature CD5+ B cells within lymphoid organs and in the peripheral blood
Deguelin activates the mitochondrial pathway of apoptosis in primary chronic lymphocytic leukemia (CLL) cells
Peripheral blood mononuclear cells (PBMCs) from 35 CLL patients (>90% CD19+, CD5+ B cells) and 10 healthy donors were treated with increasing concentrations of deguelin (0–10 μM), and cell viability was evaluated at 48 h by Annexin V/PI staining and flow cytometry
Summary
B cell chronic lymphocytic leukemia is characterized by a progressive accumulation of monoclonal mature CD5+ B cells within lymphoid organs and in the peripheral blood. By one year of age, virtually all NZB mice display a clonal hyperplasia of B220low CD5low IgM+ hyperdiploid cells that are first detected in the peritoneal cavity and progressively colonize the spleen, occasionally progressing to a lymphoid neoplasia that infiltrates other lymphoid and non-lymphoid tissues like bone marrow, lymph nodes, liver or lungs [27]. This leukemic cells have many similarities to the malignant cell in human CLL [28,29]. Deguelin remarkably potentiates fludarabine-induced dsDNA strand breaks showing a mild synergistic effect in vitro on human CLL cells and NZB CLL-like cells, and prolongs survival in an experimental model of CLL established by transfer of splenocytes from old NZB mice with leukemic hyperdiploid CD5+ B cells into young NZB recipients
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