2-(2-Phenylethyl)chromones from agarwood of Aquilaria agallocha and their inhibitory activity against KRAS mutant NSCLC
10.16438/j.0513-4870.2024-0281
- VernacularTitle:沉香中2-(2-苯乙基)色酮类成分及其抗KRAS突变NSCLC活性
- Author:
Bao-juan XING
1
;
Yi-fan FU
2
;
He CUI
3
;
Qian ZHOU
1
;
Zhi-kang WANG
4
;
Peng CAO
3
;
Fa-ping BAI
4
;
Xue-ting CAI
1
Author Information
1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
2. School of Pharmacy, Nanjing Medical University, Nanjing 210029, China
3. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
4. Nanjing Shangyuantang Chenxiang Biotechnology Co., Ltd., Nanjing 210000, China
- Publication Type:Research Article
- Keywords:
italic>Aquilaria agallocha Roxb.;
2-(2-phenylethyl)chromone;
non-small cell lung cancer;
italic>KRAS mutant;
cell cycle
- From:
Acta Pharmaceutica Sinica
2024;59(9):2519-2528
- CountryChina
- Language:Chinese
-
Abstract:
The 2-(2-phenylethyl)chromones were separated from agarwood of Aquilaria agallocha Roxb. and their anti-KRAS mutant non-small cell lung cancer (NSCLC) activities were evaluated. 2-(2-Phenyethyl)chromones in agarwood were separated and purified by silica gel, RP-18 reverse phase silica gel, MCI gel CH20P, Diol, and semi preparative HPLC chromatography techniques, while the structures of the compounds were identified by extensive spectroscopic analysis, such as 1D and 2D NMR and ESI-MS. The cell counting kit 8 (CCK-8) assay was used to screen the anti-tumor activity of the isolated monomeric compounds on three KRAS-mutant NSCLC cells. The cell proliferation, cloning formation, adhesion ability, and cell cycle arrest activity of compound 8 were analyzed. Molecular docking and Western blot experiments were used to study the mechanism of compound 8. The in vivo anti-tumor activity of the compound 8 was evaluated by zebrafish cell derived xenograft (CDX) model. Nineteen known 2-(2-phenylethyl)chromones were isolated from the ethyl acetate extract of agarwood. On A549 (KRAS G12S) cells, compounds 8, 10, and 19 showed good inhibitory activity, on H23 (KRAS G12C) cells, compounds 7, 8, and 19 showed good inhibitory activity, and on H358 (KRAS G12C) cells, compounds 8, 10, and 16 showed good inhibitory activity. Compound 8 had the best inhibitory activity in all three cell lines. It effectively inhibited cell proliferation, clone formation, adhesion ability, and arrested the H23 cell cycle at G2/M phase. Compound 8 could also inhibit the expression of c-Met and its downstream signaling pathways, effectively inhibiting tumor growth in zebrafish CDX model. In conclusion, among the nineteen known 2-(2-phenylethyl)chromones, compound 8 had the best activity and significantly inhibited the proliferation of KRAS-mutant NSCLC cells by arresting the cells in the G2/M phase.
