The Antitumor Effect and Mechanism of Total Flavonoids From Coreopsis Tinctoria Nutt (Snow Chrysanthemum) on Lung Cancer Using Network Pharmacology and Molecular Docking

Yilimire Wufuer,Guixia Wu,Xu Yang,Li Zhong,Kurexi Yunusi,Luyuan Guo,Kasimujing Aximujiang

doi:10.3389/fphar.2022.761785

Abstract

Coreopsis tinctoria Nutt (C. tinctoria), also known as Snow Chrysanthemum, is rich in polyphenols and flavonoids. It has important pharmacological effects such as lowering blood lipids, regulating blood glucose, and anti-tumor effect. However, its anti-tumor mechanism has not yet been investigated thoroughly. This study aimed to explore the anti-tumor effect of total flavonoids extracted from C. tinctoria (CTFs) on lung cancer and the possible mechanism. The components of CTFs were analyzed using Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The active components of CTFs were screened according to oral bioavailability (OB) and drug-likeness (DL). Totally, 68 components of CTFs were identified and 23 active components were screened. Network pharmacological analysis on the active components identified 288 potential targets associated with lung cancer. After protein-protein interaction (PPI) network topology analysis, 17 key protein targets including Akt1, MAPK1, TP53, Bcl-2, Caspase-3, Bax, GSK3B and CCND1 were screened. The molecular docking results showed that the active components of CTFs had good binding activity with key targets. GO and KEGG analysis of candidate targets found that the main enrichment was in PI3K/Akt-mediated intrinsic apoptotic pathways. Finally, according to the results of network pharmacology, the potential molecular mechanism of CTFs intervention in lung cancer was validated experimentally in vitro and in vivo. The experimental validation results demonstrated that the antitumor activity of CTFs on lung cancer may be related to inhibiting the PI3K-Akt signaling pathway and activating the mitochondrial-mediated apoptosis pathway.

Highlights

At present, lung cancer is one of the most prevalent malignancies worldwide
The antibodies of Caspase-3, Bax, and Bcl-2 were all obtained from Abcam (United States); those of p-PI3K, PI3K, p-Akt, and Akt were from Affinity Biosciences (Cincinnati, United States); and, that of β-actin was from Proteintech Group (Wuhan, China)
We first demonstrated that the flavonoids, the natural compounds derived from coreopsis tinctoria Nutt, induced apoptosis and suppressed non-small cell lung cancer (NSCLC) growth

Summary

Introduction

Lung cancer is one of the most prevalent malignancies worldwide. It is the common cause of cancer-associated mortality, and its 5-year survival rate is less than 15% (Hirsch et al, 2017; Ma et al, 2018). Natural compounds in plants, spices, fruits, and vegetables such as taxol, vinblastine, and camptothecin, have attracted considerable attention as potential candidates for anti-cancer agents (Dong et al, 2019; Fontana et al, 2020). These phytochemicals can affect proliferation, apoptosis, invasion, and migration of cancer cells and modulate multiple signaling pathways and networks that are often disrupted in tumor initiation, proliferation, and propagation (Kotecha et al, 2016). They have the advantages of low toxicity and low cost (Colapietro et al, 2019)

Objectives

Methods

Results

Discussion

Conclusion