4.7 Article

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

Journal

BIOCHEMICAL PHARMACOLOGY
Volume 195, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114864

Keywords

Dictamnine; c-Met; Lung adenocarcinoma; PI3K; AKT; mTOR; MAPK; Gefitinib resistance

Funding

  1. National Natural Science Founda-tion of China (NSFC) [81760264, 81960394, 81960659]
  2. Key Fund of Yunnan Basic Research Program [202001AS070024]
  3. National Key Research and Develop-ment Project [2018YFA0801404]

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Dictamnine (Dic) inhibits the growth of lung cancer cells by targeting c-Met and affecting signaling pathways. It also enhances the chemo-sensitivity of EGFR-TKI-resistant lung cancer cells to gefitinib and osimertinib.
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 mitogenactivated 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 mu M). 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.

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