Affiliation:
1. Mashhad University of Medical Sciences
2. Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences
3. Birjand University of Medical Sciences
Abstract
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 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, p53, p53 along with downregulation of Bcl-2). Importantly, the aprepitant-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 -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.
Publisher
Research Square Platform LLC
Reference38 articles.
1. Global colorectal cancer burden in 2020 and projections to 2040;Xi Y;Transl Oncol,2021
2. Hadi,Colorectal Cancer: A Review of Carcinogenesis, Global Epidemiology, Current Challenges, Risk Factors, Preventive and Treatment Strategies;Hossain MS;Cancers (Basel),2022
3. Barsouk,Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors;Rawla P;Gastroenterol Review/Przegląd Gastroenterologiczny,2019
4. Vymetalkova,5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future;Vodenkova S;Pharmacol Ther,2020
5. Kundu,5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition;Sethy C;Biomed Pharmacother,2021