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

PLoS One. 2017 Jun 1;12(6):e0177123. doi: 10.1371/journal.pone.0177123. eCollection 2017.

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 anti-apoptotic 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.

MeSH terms

  • Apoptosis / drug effects*
  • Biological Products / pharmacology*
  • Cell Line, Tumor
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Melanoma / pathology*
  • STAT3 Transcription Factor / antagonists & inhibitors*

Substances

  • Biological Products
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • JAK2 protein, human
  • Janus Kinase 2

Grants and funding

This work is supported by Hong Kong Baptist University (FRG2/15-16/002), the Health and Medical Research Fund (HMRF/14130522), the Research Grants Council (HKBU/12301115, HKBU/204612 and HKBU/201913), the French National Research Agency/Research Grants Council Joint Research Scheme (A-HKBU201/12 – Oligoswitch), National Natural Science Foundation of China (21575121), Guangdong Province Natural Science Foundation (2015A030313816), Hong Kong Baptist University Century Club Sponsorship Scheme 2016, Interdisciplinary Research Matching Scheme (RC-IRMS/15-16/03), the Science and Technology Development Fund, Macao SAR (098/2014/A2), the University of Macau (MYRG2015-00137-ICMS-QRCM, MYRG2016-00151-ICMS-QRCM and MRG044/LCH/2015/ICMS) to CHL, and National Natural Science Foundation of China (21628502).