Azelnidipine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by targeting MEK1/2

Lili Zhao; Yuhan Zhang; Ang Li; Xuebo Lu; Mingzhu Li; Qiang Yuan; Ning Yang; Xiaokun Zhao; Xin Li; Yanan Jiang; Kangdong Liu

doi:10.1016/j.omto.2022.09.007

Azelnidipine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by targeting MEK1/2

Mol Ther Oncolytics. 2022 Sep 26:27:61-72. doi: 10.1016/j.omto.2022.09.007. eCollection 2022 Dec 15.

Authors

Lili Zhao¹, Yuhan Zhang^{1

2}, Ang Li^{1

2}, Xuebo Lu^{1

2}, Mingzhu Li^{1

2}, Qiang Yuan¹, Ning Yang^{1

2}, Xiaokun Zhao^{1

2}, Xin Li¹, Yanan Jiang^{1

2

3}, Kangdong Liu^{1

2

3

4

5}

Affiliations

¹ Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China.
² China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, Henan, China.
³ State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou 450000, Henan, China.
⁴ Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou 450000, Henan, China.
⁵ Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou 450000, Henan, China.

Abstract

Epidemiological and mechanistic studies suggest that some US Food and Drug Administration (FDA)-approved drugs can reduce the incidence of cancer and inhibit tumor growth. Therefore, investigating FDA-approved drugs for cancer chemoprevention is a promising strategy. In this study, we screened FDA-approved drugs and found that azelnidipine, a Ca channel blocker widely used in the treatment of hypertension, inhibits the growth of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. We identified that MEK1/2 were direct targets of azelnidipine through pull-down assay and cellular thermal shift assay. Azelnidipine could suppress kinase activity of MEK1/2 through in vitro kinase assay. Hypophosphorylation of ERK1/2 decreased the levels of Cyclin D1/CDK6 in ESCC cells after azelnidipine treatment. More importantly, azelnidipine, like trametinib, inhibited the growth of ESCC in vivo. In conclusion, azelnidipine, a novel dual MEK1/2 inhibitor, exerted antitumor effects against ESCC cell lines and patient-derived xenograft in ESCC.

Keywords: MEK1/2 inhibitor; MEK1/2-ERK1/2 signaling pathway; azelnidipine; cell cycle; esophageal squamous cell carcinoma; proliferation.