Persistent Jak/Stat3 signal transduction plays a crucial role in
tumorigenesis and immune development. 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. While BBM has been shown to have potent antitumor activities with low toxicity in various
cancer types, the molecular mechanism of action of BBM remains largely unknown. Here, we determine the antitumor activities of 13 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 IC(50)0.69 μM. Autophosphorylation of Jak2
kinase at Tyr1007/1008 sites also was strongly inhibited in the range of 15 μM of BBMD3 in human
melanoma cells at 4h
after treatment. Following inhibition of autophosphorylation of Jak2, BBMD3 blocked constitutive activation of downstream Stat3 signaling in
melanoma cells. BBMD3 also down-regulated expression of the Stat3 target
proteins Mcl-1and Bcl-x(L), associated with induction of apoptosis. In sum, our findings demonstrate that the novel
berbamine derivative BBMD3 is an inhibitor of the Jak2/Stat3 signaling pathway, providing evidence for a molecular mechanism whereby BBMD3 exerts at least in part the apoptosis of human
melanoma cells. In addition, BBMD3 represents a promising lead compound for development of new
therapeutics for
cancer treatment.