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

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 a...

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Bibliographic Details
Published in:PloS one 2017-06, Vol.12 (6), p.e0177123-e0177123
Main Authors: Wu, Ke-Jia, Huang, Jie-Min, Zhong, Hai-Jing, Dong, Zhen-Zhen, Vellaisamy, Kasipandi, Lu, Jin-Jian, Chen, Xiu-Ping, Chiu, Pauline, Kwong, Daniel W J, Han, Quan-Bin, Ma, Dik-Lung, Leung, Chung-Hang
Format: Article
Language:English
Subjects:
Analogs
Angiogenesis
Apoptosis
Apoptosis - drug effects
Assaying
Bcl-2 protein
Biological Products - pharmacology
Biology and Life Sciences
Biotechnology
Cancer
Cancer cells
Care and treatment
Caspase
Caspase-3
Cell cycle
Cell Line, Tumor
Cellular signal transduction
Chinese medicine
Genetic aspects
Humans
Inhibition
Inhibitors
Janus kinase 2
Janus Kinase 2 - antagonists & inhibitors
Kinases
Liver cancer
Lysates
Markers
Medical research
Medicine and Health Sciences
Melanoma
Melanoma - pathology
Natural products
Phosphorylation
Poly(ADP-ribose) polymerase
Prostate cancer
Proteins
Quality
Research and Analysis Methods
Signal transduction
Skin cancer
STAT3
Stat3 protein
STAT3 Transcription Factor - antagonists & inhibitors
Therapy
Tumor cell lines
Tumorigenesis
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0177123