Efficient lysis of B-chronic lymphocytic leukemia cells by the plant-derived sesquiterpene alcohol α-bisabolol, a dual proapoptotic and antiautophagic agent
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Antonella Rigo1,2, Isacco Ferrarini1,2, Angela Bonalumi1, Cristina Tecchio1, Alessio Montresor3, Carlo Laudanna3 and Fabrizio Vinante1,2
1Section of Hematology, Department of Medicine, University of Verona, Verona, Italy
2Cancer Research and Cell Biology Laboratory, Department of Medicine, University of Verona, Verona, Italy
3Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy
Fabrizio Vinante, email: [email protected]
Keywords: apoptosis; autophagy; chronic lymphocytic leukemia; treatment; α-bisabolol
Received: March 01, 2018 Accepted: April 28, 2018 Published: May 25, 2018
The sesquiterpene α-bisabolol (α-BSB) is a cytotoxic agent against acute leukemia and chronic myeloid leukemia cells. Here the profile of α-BSB citotoxicity was evaluated ex vivo in primary mononuclear blood cells isolated from 45 untreated B-chronic lymphocytic leukemia (B-CLL) patients. We studied the effects of α-BSB by flow cytometric and western blotting techniques with the following findings: (1) α-BSB was an effective proapoptotic agent against B-CLL cells (IC50 42 ± 15 μM). It was also active, but to a lesser extent, on normal residual B cells and monocytes (IC50 68 ± 34 and 74 ± 28 μM, respectively; p < 0.01), while T-cells, though not achieving IC50, were nevertheless decreased. (2) Lipid raft content positively correlated with α-BSB cell sensitivity, while neither the phenotype of B-CLL cells nor the disease clinical stage did affect the sensitivity to α-BSB. (3) Flow cytometry analysis evidenced the induction of pores in mitochondrial and lysosomal membrane after 3- to 5-hour exposure of B-CLL cells to α-BSB, leading to apoptosis; in contrast, western blotting analysis showed inhibition of the autophagic flux. Therefore, according to cellular selectivity, α-BSB is a cytotoxic agent preferentially active against leukemic cells, while its lower activity on normal B cells, monocytes and T cells may account for an additive anti-inflammatory effect targeting the leukemia-associated pro-inflammatory microenvironment. Consistent with the observed effects on intracellular processes, α-BSB should be regarded as a dual agent, both activating mitochondrial-based apoptosis and inhibiting autophagy by disrupting lysosomes.
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