Investigation of the Role of Neurokinin-1 Receptor Inhibition Using Aprepitant in the Apoptotic Cell Death through PI3K/Akt/NF-κB Signal Transduction Pathways in Colon Cancer Cells

Abstract

Background. Colorectal cancer (CRC) is recognized as one of the most common malignancies with a high mortality rate worldwide, supporting the necessity for an effective novel antitumor drug to improve current therapy’s effectiveness. Substance P (SP) is the essential member of the tachykinins (TKs) family, which binds to the specific receptors, known as neurokinin-1 receptor (NK1R), exerting its multiple influences such as tumor cell proliferation, angiogenesis, and metastasis. Aprepitant, as a specific NK1R antagonist, is suggested as a novel antitumor agent, promoting apoptotic processes in tumor cells; however, the exact antitumor mechanism of aprepitant on molecular signaling in CRC is not entirely known. Method. The resazurin assay was conducted to assess the cytotoxic effects of aprepitant on the viability of the CRC cell line (SW480). The level of reactive oxygen species (ROS) was measured after 24-hour treatment with SP and aprepitant. PI/annexin V-FITC staining was conducted to assess apoptosis. Also, the expression of NF-κB antiapoptotic target genes and proapoptotic p53 target genes was measured by real-time- (RT-) PCR assay. Western blotting assay was performed to determine the expression of PI3k/AKT/NF-κB proteins. Results. We found that aprepitant stimulates apoptotic cell death and attenuates the PI3K/Akt pathway and its downstream proapoptotic target gene, including NF-κB in SW480 cells. Also, the obtained results from the quantitative RT-PCR assay showed that aprepitant could decrease the level of mRNA of NF-κB antiapoptotic target genes. Conclusion. Towards this end, this study suggests that SP/NK1R system plays a vital role in the development of CRC, and pharmaceutical targeting of NK1R using aprepitant might be a promising treatment against CRC.

Aprepitant Inhibits JNK and p38/MAPK to Attenuate Inflammation and Suppresses Inflammatory Pain

“…In fibroblast-like synoviocytes, aprepitant can inhibit TNFα-induced phosphorylation and degradation of IκBα, the inhibitor of NF-κBp65, as well as attenuate TNFα-induced nuclear translocation and activity of NF-κBp65 ( Liu X. et al, 2019 ). In colorectal cancer, aprepitant can inhibit the NF-κB via PI3K/AKT axis ( Ghahremanloo et al, 2021 ). These data suggest that the activity of NF-κBp65 may play an important role in the analgesic effect of aprepitant on inflammatory pain.…”

The Therapeutic Potential of Aprepitant in Glioblastoma Cancer Cells through Redox Modification

“…This finding was in accordance with the results of the previous investigations, which reported the cytotoxic property for aprepitant in several cancers ranging from solid tumors [ 35 ] to hematologic malignancies [ 36 ]. Ghahremanloo et al also suggested that a single agent of aprepitant diminishes the viability of colon cancer-derived SW480 cells by reducing the intracellular levels of ROS and abrogating the NF- κ B signaling axis [ 37 ]. In glioblastoma, Korfi et al suggested that a higher concentration of aprepitant (35 μ M) is capable of reducing ROS production while increasing the enzymatic activity of superoxidase dismutase (SOD) and catalase [ 38 ].…”

The SP/NK1R System-Mediated ROS Generation in GBM Cells through Inhibiting Glutaredoxin Protein

“…Or, in triple-negative breast cancer cells, aprepitant attenuated doxorubicin-induced ROS and, thereby, prevented cardiomyopathy [ 43 ]. In colon cancer, Ghahremanloo et al proposed that through suppressing the PI3K/Akt signaling axis and diminishing intracellular levels of ROS, aprepitant decreased the survival of SW480 cells [ 44 ]. It is hard to conclude, but perhaps, NK1R-induced ROS production in some tissues will contribute to tumorigenesis.…”