Chronic lymphocytic leukemia (CLL), a malignancy of mature B cells, remains incurable with chemotherapy. Our aim was to test if deguelin, a natural rotenoid which inhibits PI3K/AKT, could enhance the sensitivity to fludarabine of CLL cells and explore the therapeutic potential of deguelin/fludarabine combination in the inbreed New Zealand Black (NZB) mouse model of CLL. Our results indicate that deguelin induced apoptosis in cells from CLL patients in culture and showed a moderate synergy with fludarabine in cytoprotective culture conditions. Orally administered deguelin was highly effective on resident neoplasic cells in the spleens of aged NZB mice and combined administration with fludarabine prolonged the survival and reduced tumor infiltration in young NZB mice trasplanted with syngenic leukemic cells maintaining a good toxicity profile. Deguelin capacity to induce apoptosis, counteract microenvironmental survival stimuli and synergize with fludarabine suggests its potential for the treatment of CLL.
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