A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells

Ke Jia Wu, Jie Min Huang, Hai Jing Zhong, Zhen Zhen Dong, Kasipandi Vellaisamy, Jin Jian Lu, Xiu Ping Chen, Pauline Chiu, Daniel W J KWONG, Simon Q B HAN, Edmond Dik Lung MA, Chung Hang Leung

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27 Citations (Scopus)

Abstract

The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the antiapoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

Original languageEnglish
Article numbere0177123
JournalPLoS ONE
Volume12
Issue number6
DOIs
Publication statusPublished - Jun 2017

Scopus Subject Areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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