The proto-oncogene c-Myc plays critical roles in human
malignancies including
chronic myeloid leukemia (CML), suggesting that the discovery of specific agents targeting c-Myc would be extremely valuable for CML treatment.
Nitidine Chloride (NC), a natural bioactive
alkaloid, is suggested to possess anti-
tumor effects. However, the function of NC in
leukemia and the underlying molecular mechanisms have not been established. In this study, we found that NC induced erythroid differentiation, accompanied by increased expression of erythroid
differentiation markers, e. g. α-, ε-, γ-
globin, CD235a, CD71 and α-
hemoglobin stabilizing
protein (AHSP) in CML cells. We also observed that NC induced apoptosis and upregulated cleaved
caspase-3 and Parp-1 in K562 cells. These effects were associated with concomitant attenuation of c-Myc. Our study showed that NC treatment in CML cells enhanced phosphorylation of Thr58 residue and subsequently accelerated degradation of c-Myc. A specific group of
miRNAs, which had been reported to be activated by c-Myc, mediated
biological functions of c-Myc. We found that most of these
miRNAs, especially miR-17 and miR-20a showed strong decrement after NC treatment or c-Myc interference. Furthermore, overexpression of c-Myc or miR-17/20a alleviated NC induced differentiation and apoptosis in K562 cells. More importantly, NC enhanced the effects of
imatinib in K562 and primary CML cells. We further found that even
imatinib resistant CML cell line (K562/G01) and CML primary cells exhibited high sensitivity to NC, which showed potential possibility to overcome
imatinib resistance. Taken together, our results clearly suggested that NC promoted erythroid differentiation and apoptosis through c-Myc-
miRNAs regulatory axis, providing potential possibility to overcome
imatinib resistance.