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.

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.

• Authors: Hossein Javid, Amir R Afshari, Farnaz Zahedi Avval, Jahanbakhsh Asadi, Seyed Isaac Hashemy
• Journal: BioMed research international (Biomed Res Int) Vol. 2021 Pg. 8808214 ( 2021) ISSN: 2314-6141 [Electronic] United States
• PMID: 34926694 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Hossein Javid et al.

Chemical References

• Antineoplastic Agents
• NF-kappa B
• Receptors, Neurokinin-1
• Aprepitant
• Proto-Oncogene Proteins c-akt
• Caspases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Aprepitant (pharmacology)
• Caspases (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Esophageal Neoplasms (drug therapy, metabolism)
• Esophageal Squamous Cell Carcinoma (drug therapy, metabolism)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• M Phase Cell Cycle Checkpoints (drug effects)
• NF-kappa B (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Neurokinin-1 (metabolism)
• Signal Transduction (drug effects)