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The combined anti-tumor effects of 5-fluorouracil and neurokinin receptor inhibitor, aprepitant, against colorectal cancer: In vitro and in vivo study

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Abstract

Background

Colorectal cancer (CRC) is one of the world’s largest health concerns with growing global incidence and mortality. The potential value of the neurokinin-1 receptor as a therapeutic target has been reported in several tumor types, including CRC. Here we examined the potential anti-tumor effects of a clinically approved neurokinin-1 receptor antagonist, aprepitant, alone and its combination with 5-Fluorouracil (5-FU) as a first choice CRC chemotherapeutic drug, in both in vitro and in vivo models of CRC.

Methods

MTT assay was employed for assessing cell proliferation. mRNA expression levels were determined by quantitative real-time PCR (qRT-PCR). Flow cytometric analysis of apoptosis was performed using an Annexin-V/propidium iodide assay kit. We finally conducted an in vivo experiment in a mouse model of CRC to confirm the in vitro antiproliferative activity of aprepitant and 5-FU.

Results

We found that aprepitant and 5-FU significantly reduced CRC cell viability. The combination of drugs exhibited potent synergistic growth inhibitory effects on CRC cells. Moreover, aprepitant and 5-FU induced apoptosis and altered the levels of apoptotic genes (up-regulation of Bax, and p53 along with downregulation of Bcl-2). Importantly, the aprepitant and 5-FU combination showed a more pronounced impact on apoptosis and associated genes than either of the agents alone. Furthermore, aprepitant reduced tumor growth in vivo and led to significantly longer survival time, and this effect was more prominent when using the aprepitant and 5-FU combination.

Conclusions

Collectively, combinatory treatment with aprepitant and 5-FU potentially exerts synergistic growth inhibition and apoptosis induction in CRC, deserving further consideration as a novel strategy for CRC patients.

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Data availability

The data presented in this study are available on request from the corresponding author.

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Funding

This research was funded by the Mashhad University of Medical Sciences (Grant number: 4001542).

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Author notes

  1. Abbas Alalikhan and Safieh Ebrahimi contributed equally as first author.

Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Abbas Alalikhan, Safieh Ebrahimi & Seyed Isaac Hashemy

  2. Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Ali Aliee

  3. Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran

    Farshad Mirzavi

  4. Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Seyed Isaac Hashemy

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Contributions

Conceptualization, S.E. and S.I.H.; methodology, software, formal analysis and investigation, A. A., S. E., A.Aliee, F.M.; writing—original draft preparation, A. A. and S. E.; review and editing, A.Aliee, F. M, and S.I.H.; visualization, supervision, project administration, funding acquisition, S.I.H. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Seyed Isaac Hashemy.

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Alalikhan, A., Ebrahimi, S., Aliee, A. et al. The combined anti-tumor effects of 5-fluorouracil and neurokinin receptor inhibitor, aprepitant, against colorectal cancer: In vitro and in vivo study. Med Oncol 41, 70 (2024). https://doi.org/10.1007/s12032-024-02312-w

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