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.
Lili Zhao  1 ,  Yuhan Zhang  1  2 ,  Ang Li  1  2 ,  Xuebo Lu  1  2 ,  Mingzhu Li  1  2 ,  Qiang Yuan  1 ,  Ning Yang  1  2 ,  Xiaokun Zhao  1  2 ,  Xin Li  1 ,  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.
PMID: 36284716 DOI: 10.1016/j.omto.2022.09.007
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.
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