Pro-apoptotic activity of α-bisabolol in preclinical models of primary human acute leukemia cells

Background: We previously demonstrated that the plant-derived agent a-bisabolol enters cells via lipid rafts, binds to the pro-apoptotic Bcl-2 family protein BID, and may induce apoptosis. Here we studied the activity of alpha-bisabolol in acute leukemia cells. Methods: We tested ex vivo blasts from 42 acute leukemias (14 Philadelphia-negative and 14 Philadelphia-positive B acute lymphoid leukemias, Ph-/Ph+B-ALL; 14 acute myeloid leukemias, AML) for their sensitivity to a-bisabolol in 24-hour dose-response assays. Concentrations and time were chosen based on CD34(+), CD33(+) my and normal peripheral blood cell sensitivity to increasing a-bisabolol concentrations for up to 120 hours. Results: A clustering analysis of the sensitivity over 24 hours identified three clusters. Cluster 1 (14 +/- 5 mu M alpha-bisabolol IC50) included mainly Ph-B-ALL cells. AML cells were split into cluster 2 and 3 (45 +/- 7 and 65 +/- 5 mu M IC50). Ph+B-ALL cells were scattered, but mainly grouped into cluster 2. All leukemias, including 3 imatinib-resistant cases, were eventually responsive, but a subset of B-ALL cells was fairly sensitive to low a-bisabolol concentrations. a-bisabolol acted as a pro-apoptotic agent via a direct damage to mitochondrial integrity, which was responsible for the decrease in NADH-supported state 3 respiration and the disruption of the mitochondrial membrane potential. Conclusion: Our study provides the first evidence that a-bisabolol is a pro-apoptotic agent for primary human acute leukemia cells.