Nuplazid suppresses esophageal squamous cell carcinoma growth in vitro and in vivo by targeting PAK4

Yaxing Wei,Kangdong Liu,Lili Zhao,Xiangyu Wu,Zitong Wang,Wenjie Wu,Luyun He,Yin Yu,Qiang Yuan,Zigang Dong,Yanan Jiang,Jimin Zhao,Hao Zhou,Xuebo Lu

doi:10.1038/s41416-021-01651-z

Abstract

BackgroundDue to the high recurrence and low 5-year survival rates of esophageal squamous cell carcinoma (ESCC) after treatment, the discovery of novel drugs for recurrence chemoprevention is of particular importance.MethodsWe screened the FDA-approved drug library and found that Nuplazid, an atypical antipsychotic that acts as an effective 5-HT 2 A receptor inverse agonist, could potentially exert anticancer effects in vitro and in vivo on ESCC.ResultsPull-down results indicated that Nuplazid binds with p21-activated kinase 4 (PAK4), and a kinase assay showed that Nuplazid strongly suppressed PAK4 kinase activity. Moreover, Nuplazid exhibited inhibitory effects on ESCC in vivo.ConclusionsOur findings indicate that Nuplazid can suppress ESCC progression through targeting PAK4.

Highlights

Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth most common cause of cancer-related mortality worldwide [1]
The results indicated that Nuplazid exhibited more toxic effects on KYSE150 and KYSE450 cells compared to Shantou human embryonic esophageal (SHEE) cells (Fig. 1c and Fig. S1)
The results indicated that Nuplazid effectively suppressed the growth of Esophageal squamous cell carcinoma (ESCC) cells in a dose-dependent manner (Fig. 1d, e)

Summary

Introduction

Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth most common cause of cancer-related mortality worldwide [1]. Esophageal squamous cell carcinoma (ESCC) accounts for ~90% of esophageal cancers [2], and is typically treated with surgery, chemotherapy, radiotherapy and combination therapy [3, 4]. Even with treatment, the 5-year overall survival rate has been reported to be ~47%, with 49% of patients developing locoregional progression or distant progression [5, 6]. It is important to identify novel drugs with low toxicity and high efficacy to prevent the recurrence of ESCC and increase the survival rate of patients. The repositioning of drugs can overcome the challenges of high wastage, high cost, and time-consuming drug development [7, 8]. Screening drugs approved by the FDA and repositioning their anti-tumour effects have the potential to overcome several challenges associated with drug development and to guarantee rapid clinical trials

Methods

Results

Conclusion