Vortioxetine exhibits anti-glioblastoma activity via the PI3K-Akt signaling pathway

Document Type : Review Article

Authors

1 Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China

2 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China

3 School of Medicine, Hangzhou City University, Hangzhou 310015, China

Abstract

Objective(s): Glioblastoma multiforme (GBM) presents a significant challenge in oncology due to its highly aggressive nature and inherent resistance to conventional therapeutic interventions. Vortioxetine, a novel antidepressant, exhibits anticancer abilities and can traverse the blood-brain barrier. In this study, the antitumor effect and mechanism of vortioxetine on GBM cells were investigated.
Materials and Methods: Cell proliferation in GBM cells was assessed using the CCK8 and colony formation assays. Flow cytometry, western blot, and wound healing assay were used to study the mechanisms of vortioxetine. mCherry-GFP-LC3B and confocal microscopy were used to evaluate autophagic activity. RNA sequencing uses the capabilities of high-throughput sequencing methods to provide insight into the transcriptome of cells.
Results: Vortioxetine significantly inhibited the proliferation of GBM cells by inducing G1/G0 phase cell cycle arrest. Meanwhile, it also reduced the migratory capabilities of GBM cells. Furthermore, it promoted apoptotic cell death in GBM cells. In addition, it promoted autophagy in GBM cells, and autophagy inhibitors markedly enhanced its antiproliferative activities. Vortioxetine could down-regulate the expressions of PI3K and Akt, which were related to the occurrence and development of GBM. 
Conclusion: Our findings support the potential of vortioxetine as a novel therapeutic agent for GBM treatment. Vortioxetine exhibits anti-GBM activity via the PI3K-Akt signaling pathway. Meanwhile, our findings reveal autophagy inhibitors as an effective sensitizer for vortioxetine, offering new strategies for treating GBM.

Keywords

Main Subjects

References

1. Hisaoka K, Nishida A, Takebayashi M, Koda T, Yamawaki S, Nakata Y. Serotonin increases glial cell line-derived neutrophic factor release in rat C6 glioblastoma cells. Brain Res 2004; 1002: 167–170.
2. Bi J, Khan A, Tang J, Armando AM, Wu S, Zhang W, et al. Targeting glioblastoma signaling and metabolism with a repurposed brain-penetrant drug. Cell Rep 2021; 37: 109957.
3. Song T, Li H, Tian Z, Xu C, Liu J, Guo Y. Disruption of NF-kappaB signaling by fluoxetine attenuates MGMT expression in glioma cells. OncoTargets Ther 2015; 8: 2199-2208.
4. Steingart AB, Cotterchio M. Do antidepressants cause, promote, or inhibit cancers. J Clin Epidemiol 1995; 48: 1407-1412.
5. Siddiqui EJ, Thompson CS, Mikhailidis DP, Mumtaz FH. The role of serotonin in tumour growth. Oncol Rep 2005; 14: 1593–1597.
6. Wang Y, Wang X, Wang X, Wu D, Qi J, Zhang Y, et al. Imipramine impedes glioma progression by inhibiting YAP as a Hippo pathway independent manner and synergizes with temozolomide. J Cell Mol Med 2021; 25: 9350-9363.
7. Zhou J, Xu N, Liu B, Wang C, He Z, Lenahan C, et al. lncRNA XLOC013218 promotes cell proliferation and TMZ resistance by targeting the PIK3R2-mediated PI3K/AKT pathway in glioma. Cancer Sci 2022; 113: 2681-2692.
8. Dizeyi N, Hedlund P, Bjartell A, Tinzl M, Austild-Taskén K, Abrahamsson PA. Serotonin activates MAP kinase and PI3K/Akt signaling pathways in prostate cancer cell lines. Urol Oncol  2011; 29: 436-445.
9. Li M, Duan L, Wu W, Li W, Zhao L, Li A, et al. Vortioxetine hydrobromide inhibits the growth of gastric cancer cells in vivo and in vitro by targeting JAK2 and SRC. Oncogenesis 2023; 12: 24-35.
10. Schmidt L, Kling T, Monsefi N, Olsson M, Hansson C, Baskaran S, et al. Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions. Neuro Oncol 2013; 15: 1469-1478.
11. Yao T, Asayama Y. Animal-cell culture media: History, characteristics, and current issues. Reprod Med Biol 2017; 16: 99-117.
12. Cai L, Qin X, Xu Z, Song Y, Jiang H, Wu Y, et al. Comparison of cytotoxicity evaluation of anticancer drugs between real-time cell analysis and CCK-8 method. ACS Omega 2019; 4: 12036-12042.
13. Franken N, Rodermond H, Stap J, Haveman J, Bree C. Clonogenic assay of cells in vitro. Nat Protoc 2006; 1: 2315–2319. 
14. Kim H, Kim J, Yu S, Lee YY, Park J, Choi RJ, et al. A Mechanism for microRNA arm switching regulated by uridylation. Mol Cell 2020; 78: 1224-1236.
15. Pijuan J, Barceló C, Moreno DF, Maiques O, Sisó P, Marti RM, et al. In vitro cell migration, invasion, and adhesion assays: From cell imaging to data analysis. Front Cell Dev Biol 2019; 7: 107-122.
16. Edfors F, Hober A, Linderbäck K, Maddalo G, Azimi A, Sivertsson Å, et al. Enhanced validation of antibodies for research applications. Nat Commun 2018; 9: 4130-4139.
17. Hollville E, Martin SJ. Measuring apoptosis by microscopy and flow cytometry. Curr Protoc Immunol 2016; 112: 1-14.
18. Lin X, Liu YH, Zhang HQ, Wu LW, Li Q, Deng J, et al. DSCC1 interacts with HSP90AB1 and promotes the progression of lung adenocarcinoma via regulating ER stress. Cancer Cell Int 2023; 23: 208-223.
19. Koch CM, Chiu SF, Akbarpour M, Bharat A, Ridge KM, Bartom ET, et al. A Beginner’s guide to analysis of rna sequencing data. Am J Respir Cell Mol Biol 2018; 59: 145-157.
20. Ryskalin L, Limanaqi F, Biagioni F, Frati A, Esposito V, Calierno MT, et al. The emerging role of m-TOR up-regulation in brain Astrocytoma. Histol Histopathol 2017; 32: 413-431.
21. Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature 2010; 466: 68-76.
22. Tewari D, Patni P, Bishayee A, Sah AN, Bishayee A. Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: A novel therapeutic strategy. Semin Cancer Biol 2022; 80: 1-17.
23. Morgos DT, Stefani C, Miricescu D, Greabu M, Stanciu S, Nica S, et al. Targeting PI3K/AKT/mTOR and MAPK signaling pathways in gastric cancer. Int J Mol Sci 2024; 25: 1848.
24. Merzak A, Koochekpour S, Fillion MP, Fillion G, Pilkington GJ. Expression of serotonin receptors in human fetal astrocytes and glioma cell lines: A possible role in glioma cell proliferation and migration. Brain Res Mol Brain Res 1996; 41: 1-7.
25.    Cheer SM, Goa KL. Fluoxetine: A review of its therapeutic potential in the treatment of depression associated with physical illness. Drugs 2001; 61: 81-110.
26.    Hosseinimehr SJ, Najafi SH, Shafiee F, Hassanzadeh S, Farzipour S, Ghasemi A, et al. Fluoxetine as an antidepressant medicine improves the effects of ionizing radiation for the treatment of glioma. J Bioenerg Biomembr 2020; 52: 165-174.
27. Sarrouilhe D, Clarhaut J, Defamie N, Mesnil M. Serotonin and cancer: What is the link? Curr Mol Med 2015; 15: 62-77.
28. Meyer N, Henkel L, Linder B, Zielke S, Tascher G, Trautmann S, et al. Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death. Autophagy 2021; 17: 3424-3443.
29. Yin H, Lu H, Yang JH, Li Q, Li M, Zhao Q, et al. Daurisoline suppresses glioma progression by inhibiting autophagy through PI3K/AKT/mTOR pathway and increases TMZ sensitivity. Biochem Pharmacol 2024; 223: 116113.
30. Morita K, Arimochi H, Itoh H, Her S. Possible involvement of 5alpha-reduced neurosteroids in adrenergic and serotonergic stimulation of GFAP gene expression in rat C6 glioma cells. Brain Res 2006; 1085: 49-56.
31. Devare MN, Kaeberlein M. An antidepressant drug vortioxetine suppresses malignant glioblastoma cell growth. MicroPubl Biol 2024; 2024: 10-15.
32.    D’Alessandro G, Lauro C, Quaglio D, Ghirga F, Botta B, Trettel F, et al. Neuro-signals from gut microbiota: Perspectives for brain glioma. Cancers 2021; 13: 2810-2831.
33.    Zifa E, Fillion G. 5-Hydroxytryptamine receptors. Pharmacol Rev 1992; 44: 401-458.
34.    Karpel-Massler G, Kast RE, Westhoff MA, Dwucet A, Welscher N, Nonnenmacher L, et al. Olanzapine inhibits proliferation, migration and anchorage-independent growth in human glioblastoma cell lines and enhances temozolomide’s antiproliferative effect. J Neurooncol 2015; 122: 21-33.
35. Hsu FT, Chiang IT, Wang WS. Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF-kappaB signalling participate in anti-glioblastoma of imipramine. J Cell Mol Med 2020; 24: 3982-4000.
36.    Balakrishna P, George S, Hatoum H, Mukherjee S. Serotonin pathway in cancer. Int J Mol Sci 2021; 22: 1268-1277.
37.    Sorice M. Crosstalk of Autophagy and Apoptosis. Cells 2022; 11: 1479-1481.
38.Lv GB, Wang TT, Zhu HL, Wang HK, Sun W, Zhao LF. Vortioxetine induces apoptosis and autophagy of gastric cancer AGS cells via the PI3K/AKT pathway. FEBS Open Bio 2020; 10: 2157-2165.
39. Seitz C, Hugle M, Cristofanon S, Tchoghandjian A, Fulda S. The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk. Int J Cancer 2013; 132: 82-93.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 4
April 2025
Pages 401-408

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