Benzydamine, a CDK2 Kinase Inhibitor, Suppresses The Growth of Esophageal Squamous Cell Carcinoma in Vitro and in Vivo.

Background: Esophageal squamous cell carcinoma (ESCC) is among one of the leading causes of cancer death worldwide owing to late detection and low survival rate. The clinical outcome of ESCC remains dismal. To date, the disease lacks available targeted therapies. Recently, drugs approved by the Food and Drug Administration have been reported to have potential as cancer chemoprevention agents. Methods: Benzydamine, available as a hydrochloride salt, a locally acting non-steroidal anti-inflammatory drug, was screened out among FDA-approved drugs owing to its effective cytotoxic effect on KYSE450 cells, which remained unexplored. Mass spectrometry, kinase prediction and Swiss Target Prediction were used to verify the potential target(s) of benzydamine. Patient-derived oesophageal xenograft mouse model were used to investigate the effect of benzydamine on tumor growth in vivo.Results: We found that benzydamine inhibited anchorage-dependent and -independent growth of ESCC cells. Kyoto Encyclopedia of Genes and Genomes pathway enrichment revealed that benzydamine attenuated five signaling pathways, including the DNA replication pathway. We further found that benzydamine could bind to CDK2 in its ATP-binding site. Inhibition of the activity of CDK2 suppressed the growth of ESCC cells and led to a G1/S cell cycle arrest. Additionally, knocking-down CDK2 decreased the sensitivity of ESCC cells to benzydamine hydrochloride. Notably, benzydamine suppressed tumour growth in a patient-derived oesophageal xenograft mouse model of ESCC in vivo.Conclusions: We have identified CDK2 as a potential target of benzydamine for the treatment and prevention of ESCC. Benzydamine suppressed the growth of ESCC cells by inhibiting the activity of CDK2.