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http://dx.doi.org/10.4062/biomolther.2022.121

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)
Publication Information
Biomolecules & Therapeutics / v.30, no.6, 2022 , pp. 585-592 More about this Journal
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
Hydroxyzine; Reactive oxygen species; Triple-negative breast cancer; JAK2/STAT3; Cell cycle; Apoptosis;
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