Acacetin exerts antitumor effects on gastric cancer by targeting EGFR

Guangtao Zhang; Jiahuan Dong; Lu Lu; Yujing Liu; Dan Hu; Yuanmin Wu; Aiguang Zhao; Hanchen Xu

doi:10.3389/fphar.2023.1121643

Acacetin exerts antitumor effects on gastric cancer by targeting EGFR

Front Pharmacol. 2023 May 17:14:1121643. doi: 10.3389/fphar.2023.1121643. eCollection 2023.

Authors

Guangtao Zhang^{1

2}, Jiahuan Dong^{1

3}, Lu Lu^{1

2}, Yujing Liu^{1

2}, Dan Hu⁴, Yuanmin Wu⁴, Aiguang Zhao³, Hanchen Xu^{1

2}

Affiliations

¹ Longhua Hospital, Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation;, Shanghai, China.
³ Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁴ Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai, China.

Abstract

Background: Gastric cancer (GC) is a common malignant tumor with a poor prognosis. Combination treatments may prolong the survival of patients with GC. Acacetin, which is a flavonoid, exerts potent inhibitory effects on several types of cancer cells; however, the mechanisms of action remain poorly understood. Methods: Network pharmacology and RNA sequencing were used to predict the targets of acacetin, which were then verified by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and molecular docking. The biological functions of acacetin in MKN45 and MGC803 cells were investigated using TUNEL assays, crystal staining and colony formation assays. The pathways affected by acacetin were verified through reverse experiments. The in vivo antitumor efficacy of acacetin was assessed in a subcutaneous xenotransplanted tumor model. Results: In this study, we identified EGFR from more than a dozen predicted targets as a protein that directly binds to acacetin. Moreover, acacetin affected the level of phosphorylated EGFR. In vitro, acacetin promoted the apoptosis of GC cells. Importantly, EGFR agonists reversed the inhibitory effects of acacetin on the STAT3 and ERK pathways. In vivo, acacetin decreased the protein levels of pEGFR in tumors, resulting in increased GC xenograft tumor regression without obvious toxicity. Conclusion: Our findings highlight EGFR as one of the direct targets of acacetin in GC cells. Acacetin inhibited the phosphatase activity of EGFR in vitro and in vivo, which played a role in the antitumor effects of acacetin. These studies provide new evidence for the use of acacetin as a potential reagent for the treatment of GC.

Keywords: EGFR; acacetin; cell apoptosis; gastric cancer; target.

Grants and funding

This work was supported by Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No: ZYYCXTD-C-202208) Shanghai 2021“Science and Technology Innovation Action Plan” medical innovation research project, Shanghai Oncology Clinical Medical Research Center of Traditional Chinese Medicine (No. 21MC1930500) Shanghai Rising-Star Program, No. 20QA1409300 the Program for Young Eastern Scholar at Shanghai Institutions of Higher Learning, No. QD2019034. Health Science and Technology project of Shanghai Pudong New Area Health Commission, No. PW2021A-43 Shanghai Pudong New Area Health System discipline leader Training Program, No. PWRd 2021-21 Scientific research project of Shanghai Pudong New Area Science and Technology Development Fund, (PKJ2019-Y17, PKJ2022-Y41).