Novel berbamine derivatives block Jak2/Stat3 signaling, associated with induction of apoptosis on human melanoma cells

Activated Jak/Stat3 signaling has been validated as a promising molecular target for cancer therapeutics discovery and development. Berbamine (BBM), a natural bis-benzylisoquinoline alkaloid, was identified from the traditional Chinese herbal medicine Berberis amurensis used for treatment of cancer patients. Here, we determine the antitumor activities of thirteen synthetic berbamine derivatives (BBMDs) against human solid tumor cells. BBMD3, which is the most potent in this series of novel BBMDs, exhibits over 6-fold increase in biological activity compared to natural BBM. Moreover, BBMD3, directly inhibits Jak2 autophosphorylation kinase activity in vitro with IC₅₀ =0.69µM. Autophosphorylation of Jak2 kinase at Tyr1007/1008 sites also was strongly inhibited by BBMD3 in human melanoma cells. Following inhibition of autophosphorylation of Jak2, BBMD3 blocked constitutive activation of downstream Stat3 signaling in melanoma cells, associated with induction of apoptosis. In sum, our findings demonstrate that the novel BBMD3 is an inhibitor of the Jak2/Stat3 signaling pathway, suggesting evidence for a molecular mechanism whereby BBMD3 exerts at least part of apoptosis of human melanoma cells. In addition, BBMD3 represents a promising lead compound for development of new therapeutics for cancer treatment.