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.
Highlights
Colorectal cancer (CRC) constitutes one of the commonly reported malignancies with limited treatment options and a high mortality rate [1]
It is found that substance P (SP), hemokinin-1 (HK-1), neurokinin B (NKB), neurokinin A (NKA), and Nterminally extended forms of NKA, including neuropeptide γ (NPγ) and neuropeptide K (NPK), are the most important members of the family of TK neuropeptides in mammalian [10, 11]
To investigate the cell growth inhibitory effects of AP, SW480 cells were exposed to increasing concentrations of AP (0-40 μM) for 24 h and 48 h
Summary
Colorectal cancer (CRC) constitutes one of the commonly reported malignancies with limited treatment options and a high mortality rate [1]. Several observational researches have failed to indicate any therapeutic efficacy in the survival rate of CRC, despite evidence-based advances in treatment [6] Toward this end, BioMed Research International attention is focusing on developing new agents with potent antitumor properties to improve the treatment of CRC in the context of targeted therapies [7, 8]. 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; the exact antitumor mechanism of aprepitant on molecular signaling in CRC is not entirely known. 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
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