Curcumin Inhibits Proliferation of Leukemic Cells Expressing P210BCR-ABL or BCR-ABL-T315I and Prolongs Survival of Mice with B-Cell Acute Lymphoblastic Leukemia (B-ALL).

The prognosis of BCR-ABL-induced B-ALL remains dismal with no effective chemotherapies currently available. Curcumin, a natural compound derived from tumeric, has been shown to induce apoptosis in the leukemic cell line K562 and in many solid tumor cells. We tested whether curcumin has an inhibitory effect on B-lymphoid transformation by wild type BCR-ABL or BCR-ABL-T315I mutant. We first used BCR-ABL-expressing pre-B cells isolated from B-ALL mice and BCR-ABL-expressing BaF/3 cells. We treated these cells with different concentrations of curcumin (10, 30, or 50 uM), and found that proliferation of the cells was significantly inhibited at concentrations as low as 10 uM. Curcumin also induced apoptosis of the cells, as shown by increased Annexin V-positive cells detected by FACS. Western blot analysis showed that Curcumin treatment resulted in decreased JNK2 activation and a significant increase in IKKa/b expression. To further investigate the underlying mechanisms for cellular apoptosis induced by curcumin, we screened for apoptosis related transcription factors that were activated or inactivated in curcumin-treated BCR-ABL-expressing pre-B cells isolated from B-ALL mice. To do so, we probed nuclear extracts of these cells onto a commercial DNA oligonucleotide arrays (Panomics) representing the canonical binding sites for 52 transcription factors. We observed decreased expression of NFkB at 48 hours and a significant increase in expression of AP-2, p53, and vitamin D receptor 3 (VDR3) at 24 hours. The p53 induction by curcumin was further demonstrated by Western blotting. To examine the efficacy of curcumin on B-ALL, we induced B-ALL in BALB/c mice by transplanting BCR-ABL-transduced donor bone marrow cells into lethally irradiated recipient mice. The B-ALL mice were treated with intraperitoneally injected curcumin (40 mg/kg, once a day), and the treated mice survived significantly longer than the vehicle-treated B-ALL mice (p=0.04; Peto-Wilcoxon test). Taken together, our results suggest a potential use of curcumin in treating BCR-ABL-induced B-ALL.