Title:A Novel Tryptanthrin Derivative D6 Induces Apoptosis and DNA Damage in Non-small-cell Lung Cancer Cells Through Regulating the EGFR Pathway
Volume: 24
Issue: 17
Author(s): Haitao Long, Guanglong Zhang, Yue Zhou, Liqing Qin, Danxue Zhu, Jiayi Chen, Bo Liu, Huayuan Tan, Danping Chen, Zhurui Li, Chengpeng Li*Zhenchao Wang*
Affiliation:
- School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China
- Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang, 550025, China
- School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China
- Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang, 550025, China
- National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guizhou University, Guiyang, 550025, China
Keywords:
Non-small cell lung cancer, tryptanthrin derivatives, anti-cancer, apoptosis, proteomics, EGFR.
Abstract:
Background: Non-small-cell lung cancer is a prevalent malignancy associated with significant morbidity
and mortality rates. Tryptanthrin and its derivatives have exhibited potent antitumor activity.
Objective: This study aims to investigate the inhibitory effect of a novel synthesized tryptanthrin derivative D6 on
proliferation and the possible mechanism of human non-small cell lung cancer cell lines (A549) in vitro.
Methods: In this study, MTT assay, cell migration, colony formation assay, cell cycle analysis, cell apoptosis, JC-
1 staining assay, reactive oxygen species analysis, proteomics, western blotting, high content screening and absorption
titrations analysis were performed.
Results: We found that D6 inhibited both the proliferation and migration, induced cell cycle arrest in the G2/M
phase, increased levels of ROS, decreased mitochondrial membrane potential, and promoted apoptosis in A549
cells. Further mechanistic studies found that D6 reduced EGFR expression in A549 cells and inhibited the EGFR
pathway by decreasing phosphorylation levels of EGFR, Stat3, AKT and Erk1/2. Moreover, DNA damage induced
by D6 involved an increase in p53/MDM2 ratio and concentration-dependent accumulation of micronuclei.
Conclusion: D6 demonstrated significant antitumor activity against A549 cells by inhibiting the EGFR signaling
pathway, inducing DNA damage, and subsequently leading to oxidative stress, apoptosis, and cell cycle arrest.
Our findings suggest that D6 exhibits potential as an NSCLC drug, owing to its attributes such as antiproliferative
activity and ability to induce apoptosis by attenuating the EGFR-mediated signaling pathway.
