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

Overview

Journal Biomed Res Int

Publisher Wiley

Specialties Biomedical Engineering
Biotechnology
General Medicine

Date 2021 Aug 16

PMID 34395609

Citations 14

Authors

Atefeh Ghahremanloo

Hossein Javid

Amir R Afshari

Seyed Isaac Hashemy

Affiliations

Soon will be listed here.

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-B 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-B proteins.

Results: We found that aprepitant stimulates apoptotic cell death and attenuates the PI3K/Akt pathway and its downstream proapoptotic target gene, including NF-B in SW480 cells. Also, the obtained results from the quantitative RT-PCR assay showed that aprepitant could decrease the level of mRNA of NF-B 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.

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References

Mohammadi F, Soltani A, Ghahremanloo A, Javid H, Hashemy S . The thioredoxin system and cancer therapy: a review. Cancer Chemother Pharmacol. 2019; 84(5):925-935. DOI: 10.1007/s00280-019-03912-4. View

Munoz M, Rosso M, Covenas R . A new frontier in the treatment of cancer: NK-1 receptor antagonists. Curr Med Chem. 2009; 17(6):504-16. DOI: 10.2174/092986710790416308. View

Munoz M, Covenas R, Esteban F, Redondo M . The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs. J Biosci. 2015; 40(2):441-63. DOI: 10.1007/s12038-015-9530-8. View

Chen X, Ru G, Ma Y, Xie J, Chen W, Wang H . High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis. Onco Targets Ther. 2016; 9:3595-602. PMC: 4913971. DOI: 10.2147/OTT.S102356. View

Munoz M, Gonzalez-Ortega A, Salinas-Martin M, Carranza A, Garcia-Recio S, Almendro V . The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer. Int J Oncol. 2014; 45(4):1658-72. DOI: 10.3892/ijo.2014.2565. View

Akazawa T, Kwatra S, Goldsmith L, Richardson M, Cox E, Sampson J . A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas. J Neurochem. 2009; 109(4):1079-86. PMC: 2696067. DOI: 10.1111/j.1471-4159.2009.06032.x. View

Prasad S, Gupta S, Tyagi A . Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals. Cancer Lett. 2016; 387:95-105. DOI: 10.1016/j.canlet.2016.03.042. View

Esteban F, Munoz M, Gonzalez-Moles M, Rosso M . A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage. Cancer Metastasis Rev. 2006; 25(1):137-45. DOI: 10.1007/s10555-006-8161-9. View

Yang C, Planchon S, Wuerzberger-Davis S, Davis T, Cuthill S, Miyamoto S . Coordinate modulation of Sp1, NF-kappa B, and p53 in confluent human malignant melanoma cells after ionizing radiation. FASEB J. 2000; 14(2):379-90. DOI: 10.1096/fasebj.14.2.379. View

10.

Afshari A, Karimi Roshan M, Soukhtanloo M, Ghorbani A, Rahmani F, Jalili-Nik M . Cytotoxic effects of auraptene against a human malignant glioblastoma cell line. Avicenna J Phytomed. 2019; 9(4):334-346. PMC: 6612248. View

11.

Worthley D, Leggett B . Colorectal cancer: molecular features and clinical opportunities. Clin Biochem Rev. 2010; 31(2):31-8. PMC: 2874430. View

12.

Johnson S, Gulhati P, Rampy B, Han Y, Rychahou P, Doan H . Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg. 2010; 210(5):767-76, 776-8. PMC: 2895913. DOI: 10.1016/j.jamcollsurg.2009.12.008. View

13.

Hesketh P, Grunberg S, Gralla R, Warr D, Roila F, de Wit R . The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052.... J Clin Oncol. 2003; 21(22):4112-9. DOI: 10.1200/JCO.2003.01.095. View

14.

Rahmani F, Avan A, Hashemy S, Hassanian S . Role of Wnt/β-catenin signaling regulatory microRNAs in the pathogenesis of colorectal cancer. J Cell Physiol. 2017; 233(2):811-817. DOI: 10.1002/jcp.25897. View

15.

Lorestani S, Ghahremanloo A, Jangjoo A, Abedi M, Hashemy S . Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in colorectal cancer. Mol Biol Rep. 2020; 47(5):3469-3474. DOI: 10.1007/s11033-020-05432-4. View

16.

Yaghoubi N, Soltani A, Ghazvini K, Hassanian S, Hashemy S . PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer. Biomed Pharmacother. 2018; 110:312-318. DOI: 10.1016/j.biopha.2018.11.105. View

17.

Javid H, Asadi J, Avval F, Afshari A, Hashemy S . The role of substance P/neurokinin 1 receptor in the pathogenesis of esophageal squamous cell carcinoma through constitutively active PI3K/Akt/NF-κB signal transduction pathways. Mol Biol Rep. 2020; 47(3):2253-2263. DOI: 10.1007/s11033-020-05330-9. View

18.

Munoz M, Rosso M, Robles-Frias M, Salinas-Martin M, Rosso R, Gonzalez-Ortega A . The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines. Lab Invest. 2010; 90(8):1259-69. DOI: 10.1038/labinvest.2010.92. View

19.

Bayati S, Bashash D, Ahmadian S, Safaroghli-Azar A, Alimoghaddam K, Ghavamzadeh A . Inhibition of tachykinin NK receptor using aprepitant induces apoptotic cell death and G1 arrest through Akt/p53 axis in pre-B acute lymphoblastic leukemia cells. Eur J Pharmacol. 2016; 791:274-283. DOI: 10.1016/j.ejphar.2016.09.006. View

20.

Ebrahimi S, Soltani A, Hashemy S . Oxidative stress in cervical cancer pathogenesis and resistance to therapy. J Cell Biochem. 2018; 120(5):6868-6877. DOI: 10.1002/jcb.28007. View