Repositioning of aripiprazole, an anti‑psychotic drug, to sensitize the chemotherapy of pancreatic cancer

Cho,Ye Jin; Han,Beom Seok; Ko,Soyeon; Park,Min Seok; Lee,Yun Ji; Kim,Sang Eun; Lee,Pureunchowon; Go,Han Gyeol; Park,Shinyoung; Lee,Hyunho; Kim,Sohee; Park,Eun-Ran; Jung,Kyung Hee; Hong,Soon-Sun

doi:10.3892/ijmm.2024.5458

Repositioning of aripiprazole, an anti‑psychotic drug, to sensitize the chemotherapy of pancreatic cancer

Authors:
- Ye Jin Cho
- Beom Seok Han
- Soyeon Ko
- Min Seok Park
- Yun Ji Lee
- Sang Eun Kim
- Pureunchowon Lee
- Han Gyeol Go
- Shinyoung Park
- Hyunho Lee
- Sohee Kim
- Eun-Ran Park
- Kyung Hee Jung
- Soon-Sun Hong
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Affiliations: Department of Biomedical Sciences, College of Medicine and Program in Biomedical Science and Engineering, Inha University, Incheon 22332, Republic of Korea, Department of Biomedical Sciences, College of Medicine and Program in Biomedical Science and Engineering, Inha University, Incheon 22332, Republic of Korea, Anti‑cancer Strategy Research Institute, VSPharmTech, Inc., Seoul Technopark, Seoul 01811, Republic of Korea
Published online on: November 12, 2024 https://doi.org/10.3892/ijmm.2024.5458
Article Number: 17
Copyright: © Cho et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited therapeutic options. Cisplatin is a primary chemotherapeutic agent utilized in combination with other drugs or radiotherapy for PDAC treatment. However, the severe side effects of cisplatin often necessitate discontinuation of therapy and drug resistance in tumor cells poses significant clinical challenges. Therefore, the development of effective therapeutic strategies is imperative. The present study investigated whether repositioning of the antipsychotic drug aripiprazole could sensitize the anticancer activity of cisplatin in pancreatic cancer at doses calculated by the combination index. The findings indicated that aripiprazole combined with cisplatin to suppress pancreatic cancer cell growth. Notably, the combination notably increased the expression of apoptosis markers, including cleaved caspase‑3, compared with cisplatin alone. Additionally, this combination effectively decreased XIAP and MCL‑1 expression via mitochondrial membrane potential change as revealed by JC‑1 assay, thereby inducing apoptosis. Furthermore, in fluid shear stress assay, the combination of aripiprazole and cisplatin notably inhibited cell adhesion and tumor spheroid formation. Mechanistically, phospho‑kinase array profiles showed that the enhanced anticancer efficacy of the combination treatment could be attributed to the inhibition of STAT3 signaling, which led to a significant reduction in tumor growth in a pancreatic cancer animal model. The results showed that the repositioning of aripiprazole inhibits cancer cell growth by blocking the STAT3 signaling pathway and effectively enhancing cisplatin‑induced apoptosis, thereby suggesting that the combination of aripiprazole and cisplatin may be a potent chemotherapeutic strategy for the treatment of pancreatic cancer.

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