Repurposing fluoxetine to treat lymphocytic leukemia: Apoptosis induction, sigma-1 receptor upregulation, inhibition of IL-2 cytokine production, and autophagy induction

ABSTRACT

Background

Childhood cancer has a cure rate of as low as 15% in low-income countries, suggesting a need for cheaper treatment options. Fluoxetine is a thoroughly safety-tested drug that may target the sigma-1 receptor (σ1-R).

Research design and methods

Using the human leukemic cell line, Jurkat, we investigated the effects of fluoxetine on cell survival using XTT and trypan blue staining. Apoptosis was measured using AnnexinV/PI staining and western blot analysis of caspase cleavage. IL-2 secretion of Jurkat cells in response to PHA/PMA was measured using ELISA, and the expression of AKT/pAKT and the σ1-R were measured using western blotting.

Results

Fluoxetine-induced apoptosis and G-2 cell cycle arrest. Fluoxetine reduced IL-2 secretion dose-dependently and could be further potentiated by σ1-R antagonist BD1047 (P < 0.05). Fluoxetine inhibited pAKT six hours post-treatment (P < 0.05). The expression of the σ1-R showed a significant increase between 12 to 48 hours in Jurkat cells (P < 0.05). At the same time, there was a substantial increase in autophagy.

Conclusions

Fluoxetine may have the potential for acute leukemia treatment. Co-treatment with a σ1-R antagonist increases fluoxetine-induced apoptosis, possibly targeting AKT phosphorylation and autophagy activation.

KEYWORDS:

• Acute lymphocytic leukemia
• autophagy
• cancer
• childhood cancer
• sigma-1 receptor

Acknowledgments

Part of this work was previously presented as a poster at the Drug Repurposing II conference in 2022 London, UK. (http://doi.org/10.13140/RG.2.2.18126.95040) Organised by the Biochemical Society. JM Brimson was supported by the Rachadapisek Sompote Fund for Postdoctoral Fellowship, Chulalongkorn University. C Chomchoei was supported by the 90th Anniversary of Chulalongkorn University Fund (Ratchadaphiseksomphot Endowment Fund).

Author contributions

C Chomchoei: Investigation, Formal analysis, Writing - Original Draft. JM Brimson: Conceptualization, Investigation, Formal analysis, Writing - Original Draft, Writing - Review & Editing, S Brimson: Conceptualization, Methodology, Supervision Project administration, Funding acquisition.

All authors have seen the final draft and approved its submission to Expert Opinion on Therapeutic Targets. All authors are willing to take responsibility for the data contained herein.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethical approval

Ethical approval was not needed for this study.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2022.2166829

Additional information

Funding

This study was funded by was supported by the 90th Anniversary of Chulalongkorn University Fund. (Ratchadaphiseksomphot Endowment Fund).