ARIPIPRAZOLE'S POTENTIAL ROLE IN SKIN CANCER: INVESTIGATING PYROPTOSIS AND IMMUNE PATHWAYS
Authors: Hou *Po-Hsun , Lin Yu-Chen , Chang Yu-Teng 
Published: February 2025

Abstract

Background
Skin cancer, driven by UV radiation exposure, is an escalating public health concern1. Aripiprazole, a second-generation antipsychotic, acts as a serotonin 5-HT1A partial dopamine D2 agonist and a 5-HT2A antagonist2.Although primarily used for the treatment of mental health disorders3, aripiprazole has shown promise as an anti-cancer agent in certain studies4. This study aims to investigate the effect of aripiprazole on skin cancer cells, specifically delving into pyroptosis, an inflammatory form of programmed cell death. Furthermore, we explore the role of key signaling pathways, including MAPK, TNF-α, and AIM2, to unravel the mechanisms underlying aripiprazole's action and its implications for skin cancer treatment.

Aim & Objective
The primary aim of this study is to evaluate aripiprazole's anti-skin cancer properties and its association with pyroptosis and immune-related pathways. Our objectives include assessing aripiprazole's impact on cell viability, clarifying the nature of cell death induced by aripiprazole, investigating changes in gene expression and critical signaling pathways, and evaluating aripiprazole's potential to enhance the immune response in the tumor microenvironment.

Method
The study evaluated the effects of aripiprazole on cell viability in skin cancer cells at various concentrations (0-80 μ M) for a duration of 24 hours. To assess apoptosis, A375 cells were treated with 20 μ M aripiprazole for 48 hours and analyzed using Annexin V/7-AAD staining. Western blotting analysis was performed on A375 cells treated with varying concentrations of aripiprazole to observe pyroptosis markers. Additionally, the study demonstrated the regulated signaling pathway of pyroptosis.

Results
A375 cells demonstrated an IC50 of approximately 20 μ M for aripiprazole, with a significant increase in apoptosis (65.8%) following treatment. Interestingly, crucial apoptotic proteins exhibited decreasing trends, prompting inquiries into the nature of cell death. Gene expression analysis unveiled substantial impacts on immune-related pathways, including the NOD-like receptor, Toll-like receptor, MAPK, and TNF-a signaling pathways. Western blot analysis indicated heightened expression of pyroptosis-related proteins, including cleaved Gasdermin D, caspase-1, and IL-1β, while AIM2 showed a notable upregulation.

Discussion & Conclusion
Aripiprazole shows promise as a therapeutic option in skin cancer treatment. Its distinct effects on cell viability, induction of pyroptosis, and alterations in immune-related pathways warrant further investigation.Our findings suggest that aripiprazole has potential as an anti-skin cancer agent and induce pyroptosis in A375 cells. The study reveals significant influence on immune-related pathways, implying a connection between aripiprazole and the immune system. These results open novel avenues for skin cancer treatment and emphasize the potential role of pyroptosis as a mechanism for future therapies.

References
1.D'Orazio, J., Jarrett, S., Amaro-Ortiz, A. &Scott, T. UV radiation and the skin. Int J Mol Sci14, 12222- 12248 (2013). https://doi.org:10.3390/ijms1406122222
2.Shapiro, D. A. et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology28, 1400-1411 (2003). https://doi.org:10.1038/sj.npp.13002033
3.Tuplin, E. W. &Holahan, M. R. Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity. Curr Neuropharmacol15, 1192-1207 (2017). https://doi.org:10.2174/1570159X156661704131157544 4. Suzuki, S. et al. Aripiprazole, an Antipsychotic and Partial Dopamine Agonist, Inhibits Cancer Stem Cells and Reverses Chemoresistance. Anticancer Res36, 5153-5161 (2016). https://doi.org:10.21873/anticanres.11085