Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Hydroxyzine Induces Cell Death in Triple-Negative Breast Cancer Cells via Mitochondrial Superoxide and Modulation of Jak2/STAT3 Signaling

  • Shakya, Rajina (College of Pharmacy, Daegu Catholic University) ;
  • Park, Gyu Hwan (College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Joo, Sang Hoon (College of Pharmacy, Daegu Catholic University) ;
  • Shim, Jung-Hyun (College of Pharmacy, Mokpo National University) ;
  • Choi, Joon-Seok (College of Pharmacy, Daegu Catholic University)
  • Received : 2022.09.17
  • Accepted : 2022.10.01
  • Published : 2022.11.01
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Abstract

Treatment of triple-negative breast cancer (TNBC) has been limited due to the lack of molecular targets. In this study, we evaluated the cytotoxicity of hydroxyzine, a histamine H1 receptor antagonist in human triple-negative breast cancer BT-20 and HCC-70 cells. Hydroxyzine inhibited the growth of cells in dose- and time-dependent manners. The annexin V/propidium iodide double staining assay showed that hydroxyzine induced apoptosis. The hydroxyzine-induced apoptosis was accompanied down-regulation of cyclins and CDKs, as well as the generation of reactive oxygen species (ROS) without cell cycle arrest. The effect of hydroxyzine on the induction of ROS and apoptosis on TNBC cells was prevented by pre-treatment with ROS scavengers, N-acetyl cysteine or Mito-TEMPO, a mitochondria-targeted antioxidant, indicating that an increase in the generation of ROS mediated the apoptosis induced by hydroxyzine. Western blot analysis showed that hydroxyzine-induced apoptosis was through down-regulation of the phosphorylation of JAK2 and STAT3 by hydroxyzine treatment. In addition, hydroxyzine induced the phosphorylation of JNK and p38 MAPK. Our results indicate that hydroxyzine induced apoptosis via mitochondrial superoxide generation and the suppression of JAK2/STAT3 signaling.

Keywords

Acknowledgement

This research was supported by Basic Science Research program through the National Research Foundation Korea Funded by the Ministry of Education, Science and Technology (NRF-2018R1D1A1A02050495 and NRF-2021R1A2C1014399).

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