Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways

Yu, J. et al. (2022) Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. Biochemical Pharmacology, 195, 114864. (doi: 10.1016/j.bcp.2021.114864) (PMID:34861243)

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Abstract

Dictamnine (Dic), a naturally occurring small-molecule furoquinoline alkaloid isolated from the root bark of Dictamnus dasycarpus Turcz., is reported to display anticancer properties. However, little is known about the direct target proteins and anticancer mechanisms of Dic. In the current study, Dic was found to suppress the growth of lung cancer cells in vitro and in vivo, and to attenuate the activation of PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) signaling pathways by inhibiting the phosphorylation and activation of receptor tyrosine kinase c-Met. Moreover, the binding of Dic to c-Met was confirmed by using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay. Among all cancer cell lines tested, Dic inhibited the proliferation of c-Met-dependent EBC-1 cells with the greatest potency (IC50 = 2.811 μM). Notably, Dic was shown to synergistically improve the chemo-sensitivity of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant lung cancer cells to gefitinib and osimertinib. These results suggest that Dic is a c-Met inhibitor that can serve as a potential therapeutic agent in the treatment of lung cancer, especially against EGFR TKI-resistant and c-Met-dependent lung cancer.

Item Type:Articles
Additional Information:This research was funded by the National Natural Science Foundation of China (NSFC) (grant number 81760264, 81960394 and 81960659), the Key Fund of Yunnan Basic Research Program (grant number 202001AS070024), the National Key Research and Development Project (grant number 2018YFA0801404).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ward, Dr Richard
Authors: Yu, J., Zhang, L., Peng, J., Ward, R., Hao, P., Wang, J., Zhang, N., Yang, Y., Guo, X., Xiang, C., An, S., and Xu, T.-R.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Biochemical Pharmacology
Publisher:Elsevier
ISSN:0006-2952
ISSN (Online):1873-2968
Published Online:30 November 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Biochemical Pharmacology 195: 114864
Publisher Policy:Reproduced under a Creative Commons License

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