α-bisabolol Is an Effective Proapoptotic Agent against BCR-ABL(+) Cells in Synergism with Imatinib and Nilotinib.

We showed that a-bisabolol is active against primary acute leukemia cells, including BCR-ABL+ acute lymphoblastic leukemias (ALL). Here we studied the activity of a-bisabolol against BCR-ABL+ cells using 3 cell lines (K562, LAMA-84, CMLT1) and 10 primary BCR-ABL+ ALL samples. We found that: (a) a-bisabolol was effective in reducing BCR-ABL+ cell viabilty at concentrations ranging from 53 to 73 mM; (b) a-bisabolol concentrations in BCR-ABL+ cellular compartments were 4- to 12- fold higher than in normal cells, thus indicating a preferential intake in neoplastic cells; (c) a-bisabolol displayed a slight to strong synergism with the Tyrosine Kinase Inhibitors (TKI) imatinib and nilotinib: the combination of a-bisabolol+imatinib allowed a dose reduction of each compound up to 7.2 and 9.4-fold respectively, while the combination of abisabolol+ nilotinib up to 6.7 and 5-fold respectively; (d) a-bisabolol-induced apoptosis was associated with loss of plasma membrane integrity, irreversible opening of mitochondrial transition pore, disruption of mitochondrial potential, inhibition of oxygen consumption and increase of intracellular reactive oxygen species. These data indicate a-bisabolol as a candidate for treatment of BCR-ABL+ leukemias to overcome resistance to TKI alone and to target leukemic cells through BCR-ABLindependent pathways.