Journal
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
Volume 81, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.etap.2020.103542
Keywords
Cucurbitacin IIb (CuIIb); Epidermal growth factor receptor (EGFR); Tyrosine kinase inhibitor (TKI); Apoptosis; Cell cycle arrest; Binding mode
Funding
- National Natural Science Foundation of China [31871717, 31972160, U19A2035]
- National Key Research and Development Program of China [2018YFD0300201]
- Science and Technology Development Project Foundation of Jilin Province [20200201204JC]
- Science and Technology Projects of Jilin Provincial Department of Education in the 13th Five-Year Plan [JJKH20190112KJ]
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CuIIb was confirmed to induce apoptosis and inhibit proliferation in A549 cells via the STAT3 pathway, as well as suppress cell cycle and induce G2/M phase cell cycle arrest. CuIIb also suppressed the EGFR/MAPK pathway signal transmitting, highlighting its potential as an EGFR tyrosine kinase inhibitor.
Epidermal growth factor receptor (EGFR) is considered as a valid target in the clinical trials of anticancer therapy and tyrosine kinase inhibitors (TKIs) of EGFR are approved for cancer treatments. In present work, cucurbitacin IIb (CuIIb) was confirmed to exhibit the proliferation inhibitory activity in A549 cells. CuIIb induced apoptosis via STAT3 pathway, which was mitochondria-mediated and caspase-dependent. CuIIb also suppressed the cell cycle and induced G2/M phase cell cycle arrest. CuIIb was capable of suppressing the signal transmitting of the EGFR/mitogen-activated protein kinase (MAPK) pathway which was responsible for the apoptosis and cell cycle arrest. Homogeneous time-resolved fluorescence (HTRF) analysis demonstrated that the kinase activity of EGFR was inhibited by CuIIb. Molecular docking suggested that the CuIIb-EGFR binding fundamentally depends on the contribution of both hydrophobic and hydrogen-bonding interactions. Hence CuIIb may serve as a potential EGFR TKI.
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