Aprepitant Promotes Caspase-Dependent Apoptotic Cell Death and G2/M Arrest through PI3K/Akt/NF-κB Axis in Cancer Stem-Like Esophageal Squamous Cell Carcinoma Spheres.

Hossein Javid,Farnaz Zahedi Avval,Seyed Isaac Hashemy,Amir R Afshari,Jahanbakhsh Asadi,Miguel Muñoz

doi:10.1155/2021/8808214

Abstract

The antagonists of the neurokinin-1 receptor (NK1R) are known for their anti-inflammatory, anxiolytic, antiemetic, and anticancer activities. Aprepitant, a nonpeptide NK1R antagonist, is used in nausea and vomiting, the most common side effects of cancer chemotherapy in patients. It has been established that NK1R activation by substance P (SP), which links cancer promotion and progression to a neurokinin-mediated environment, became one mechanism that corresponds to the mitogenesis of tumor cells. Therefore, this study is aimed at explaining and evaluating the anticancer impacts of aprepitant on esophageal squamous cancer cell (ESCC) spheres by using in vitro experiments, such as resazurin, ROS, annexin-V binding, RT-PCR, and Western blot analysis. As a result, we showed that aprepitant had strong antiproliferative and cytotoxic effects on ESCC cell spheres. Also, aprepitant caused significant G2-M cell cycle arrest depending on concentration increase. Further, exposure of cells to this agent resulted in caspase -8/-9-dependent apoptotic pathway activation by modifying the expression of genes involved in apoptosis. Besides, treatment of the cells by aprepitant abrogates of the PI3K/Akt pathway, as shown by reducing the level of Akt, induces apoptotic cell death. In summary, pharmacological inhibition of NK1R with aprepitant seems to have a significant chance of treating ESCC as a single agent or in conjunction with other chemotherapeutic drugs.

Highlights

Esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype of esophagus cancer, which constitutes more than 90% of this malignancy [1]
There is a side population of cells characterized by self-renewal ability, differentiation potential, high tumorigenicity, and therapy resistance, known as cancer stem cells (CSCs) [4, 5]
The sphere cells characterized by pluripotency gene overexpression and anchorage-independent proliferation were chosen as cancer stem cell-like cells (CSC-LCs) in the experiments

Summary

Introduction

Esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype of esophagus cancer, which constitutes more than 90% of this malignancy [1]. Given the ongoing progress of therapies, like surgery and chemoradiation, the overall survival rate of affected patients remains dismal because of treatment failure and high risk of recurrence. It is, critically necessary to clarify its pathogenesis and to identify efficient agents as emerging chemotherapeutic potential therapies for its prevention, diagnosis, and treatment [2, 3]. There are still no drugs in clinics available to target CSCs ; chemotherapy for advanced or recurrent ESCC is the primary approach of palliative treatment [7, 8].

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Conclusion