Novel synthetic derivatives of the natural product berbamine inhibit Jak2/Stat3 signaling and induce apoptosis of human melanoma cells

Sangkil Nam, Jun Xie, Angela Perkins, Yuelong Ma, Fan Yang, Jun Wu, Yan Wang, Rong zhen Xu, Wendong Huang, David A. Horne, Richard Jove

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

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 IC500.69μM. Autophosphorylation of Jak2 kinase at Tyr1007/1008 sites also was strongly inhibited in the range of 15μM 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-xL, 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.

Original languageEnglish (US)
Pages (from-to)484-493
Number of pages10
JournalMolecular Oncology
Volume6
Issue number5
DOIs
StatePublished - Oct 2012

Bibliographical note

Funding Information:
We thank AstraZeneca for generously providing AZD01. We thank our lab colleagues for helpful technical suggestions and critically discussing our data. We thank Analytical Cytometry Core of City of Hope for apoptosis analysis. We also thank Synthetic and Biopolymer Chemistry Core of City of Hope for synthesis of BBMDs. This study was supported by NIH grant R01 CA115674-05 to RJ.

Keywords

  • Apoptosis
  • Berbamine derivatives (BBMDs)
  • Jak2
  • Stat3

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