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Neurokinin-1 receptor antagonist aprepitant regulates autophagy and apoptosis via ROS/JNK in intrahepatic

Yang Yang1, Xueyan Cao1, Yuting Wang1

  • 1Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Liver International : Official Journal of the International Association for the Study of the Liver
|March 30, 2024
PubMed
Abstract

Insights

Aprepitant shows cytotoxic effects on intrahepatic cholangiocarcinoma (iCCA) by inducing apoptosis and autophagy. This study investigates aprepitant

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Intrahepatic cholangiocarcinoma (iCCA) presents a poor prognosis with limited therapeutic strategies.
  • Aprepitant, a neurokinin-1 receptor (NK-1R) antagonist, exhibits anti-tumorigenic properties in various cancer models.
  • The potential of aprepitant in treating iCCA remains largely unexplored.

Purpose of the Study:

  • To investigate the expression of Substance P/NK-1R (SP/NK-1R) in iCCA.
  • To evaluate the cytotoxic effects of aprepitant on iCCA cells in vitro and in vivo.
  • To elucidate the underlying molecular mechanisms of aprepitant's action in iCCA.

Main Methods:

  • Immunohistochemistry was used to assess SP/NK-1R expression in clinical iCCA samples.
  • In vitro cytotoxicity was evaluated using MTT, EdU, and colony formation assays on iCCA cell lines (HCCC-9810, RBE).
  • In vivo efficacy was assessed using a subcutaneous xenograft mouse model, with mechanistic studies involving flow cytometry, western blotting, ROS detection, and JC-1 staining.

Main Results:

  • SP/NK-1R was significantly expressed in iCCA tissues.
  • Aprepitant demonstrated dose-dependent inhibition of iCCA cell viability and xenograft growth.
  • Aprepitant induced mitochondria-dependent apoptosis via the ROS/JNK pathway and triggered dynamic autophagosome changes.

Conclusions:

  • SP/NK-1R signaling is activated in iCCA and contributes to tumor proliferation.
  • Aprepitant effectively inhibits iCCA growth by inducing apoptosis and autophagy.
  • The mechanism involves ROS accumulation and subsequent JNK pathway activation.
Keywords:
apoptosisaprepitantautophagyintrahepatic cholangiocarcinoma

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