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Aprepitant inhibits the development and metastasis of gallbladder cancer via ROS and MAPK activation
Xueyan Cao1, Yang Yang1, Wei Zhou2
1Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, 121 Jiangjiayuan Road, Gulou District, Nanjing, Jiangsu, China.
Background:
Aprepitant, as a neurokinin-1 receptor (NK-1R) antagonist, originally applied for curing chemotherapy-induced nausea and vomiting, has been reported to have significant antitumor effect on several malignant tumors. However, the effect of aprepitant on gallbladder cancer (GBC) is not clear yet. This study aimed to investigate the anti-tumor activity of aprepitant on GBC and the potential mechanisms.
Methods:
The NK-1R expression of gallbladder cancer cells were examined by immunofluorescence. MTT assay, wound healing and transwell migration assay were applied to detect the effect of aprepitant on cell proliferation, migration and invasion. Flow cytometry was used to detect the apoptosis rate. The effects of aprepitant on the expressions of cytokine were examined by real-time quantitative PCR and MAPK activation were detected via immunofluorescence and western blotting. Besides, xenograft model was established to investigate the effect of aprepitant in vivo.
Results:
Our results indicated that NK-1R was markedly expressed in gallbladder cancer cells and aprepitant effectively inhibited the proliferation, migration and invasion. Furthermore, the apoptosis, ROS and inflammation response were significantly boosted by aprepitant in GBC. Aprepitant induced NF-κB p65 nuclear translocationin and increased the expressions of p-P65, p-Akt, p-JNK, p-ERK and p-P38, as well as the mRNA levels of inflammatory cytokines IL-1β, IL-6 and TNF-α. Consistently, aprepitant suppressed the growth of GBC in xenograft mice model.
Conclusion:
Our study demonstrated that aprepitant could inhibit the development of gallbladder cancer via inducing ROS and MAPK activation, which suggested that aprepitant may become a promising therapeutic drug against GBC.
Insights
Aprepitant, a neurokinin-1 receptor antagonist, effectively inhibits gallbladder cancer (GBC) growth by inducing cell death and inflammation. This study suggests aprepitant
Area of Science:
- Oncology
- Pharmacology
Background:
- Neurokinin-1 receptor (NK-1R) antagonists like aprepitant show antitumor potential.
- The efficacy of aprepitant in gallbladder cancer (GBC) remains unexplored.
Purpose of the Study:
- To investigate the anti-tumor activity of aprepitant on GBC.
- To elucidate the underlying mechanisms of aprepitant's action in GBC.
Main Methods:
- Examined NK-1R expression in GBC cells.
- Assessed aprepitant's effects on cell proliferation, migration, invasion, and apoptosis using MTT, wound healing, Transwell, and flow cytometry assays.
- Analyzed cytokine expression and MAPK pathway activation via qPCR, immunofluorescence, and Western blotting.
- Evaluated aprepitant's efficacy in a GBC xenograft mouse model.
Main Results:
- NK-1R is highly expressed in GBC cells.
- Aprepitant significantly inhibited GBC cell proliferation, migration, and invasion.
- Aprepitant induced apoptosis, increased reactive oxygen species (ROS), and boosted inflammation.
- Aprepitant activated the NF-κB and MAPK pathways (Akt, JNK, ERK, p38) and increased inflammatory cytokine mRNA levels (IL-1β, IL-6, TNF-α).
- Aprepitant suppressed GBC tumor growth in vivo.
Conclusions:
- Aprepitant demonstrates significant anti-GBC activity.
- The mechanism involves ROS induction and MAPK pathway activation.
- Aprepitant shows promise as a therapeutic agent for gallbladder cancer.
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