Abstract
In this study, we examined the antileukemic effects of pterostilbene, a natural methylated polyphenol analog of resveratrol that is predominantly found in berries and nuts, using various human and murine leukemic cells, as well as bone marrow samples obtained from patients with leukemia. Pterostilbene administration significantly induced apoptosis of leukemic cells, but not of non-malignant hematopoietic stem/progenitor cells. Interestingly, pterostilbene was highly effective in inducing apoptosis of leukemic cells harboring the BCR/ABL fusion gene, including ABL tyrosine kinase inhibitor (TKI)-resistant cells with the T315I mutation. In BCR/ABL+ leukemic cells, pterostilbene decreased the BCR/ABL fusion protein levels and suppressed AKT and NF-κB activation. We further demonstrated that pterostilbene along with U0126, an inhibitor of the MEK/ERK signaling pathway, synergistically induced apoptosis of BCR/ABL+ cells. Our results further suggest that pterostilbene-promoted downregulation of BCR/ABL involves caspase activation triggered by proteasome inhibition-induced endoplasmic reticulum stress. Moreover, oral administration of pterostilbene significantly suppressed tumor growth in mice transplanted with BCR/ABL+ leukemic cells. Taken together, these results suggest that pterostilbene may hold potential for the treatment of BCR/ABL+ leukemia, in particular for those showing ABL-dependent TKI resistance.
Highlights
ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL)[1,2,3]
We further assessed the apoptosis-inducible effect of pterostilbene using frozen bone marrow mononuclear cells (BMMNCs) isolated from four patients: three with CML in the chronic phase at diagnosis and one with relapsed ALL harboring the T315I ABL mutation
We found that pterostilbene, a natural polyphenolic compound and a methylated analog of resveratrol, significantly induces apoptosis in BCR/ABL+ cells, including of dasatinib-resistant cells harboring the T315I ABL mutation
Summary
ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL)[1,2,3]. Dietary stilbenes comprise a class of natural compounds that display significant biological activities of medicinal interest[6]. Recent reports have further demonstrated the antiproliferative and proapoptotic activities of resveratrol against various human cancers, including leukemia[7,9]. Pterostilbene has been reported to exhibit anticancer activities via various mechanisms in several common malignant tumors, including hematologic m alignancies[13,14,15,16,17,18,19]. We explored the therapeutic potential of pterostilbene on various hematological malignancies, especially in BCR/ABL+ leukemia, and explored the underlying molecular and cellular mechanism by which pterostilbene exerts its effects on these leukemic cells
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