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Repurposing autophagy regulators in brain tumors
Edgar Petrosyan1,2, Jawad Fares1,2, Alex Cordero1,2
1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Abstract:
Malignant brain tumors, such as glioblastoma multiforme (GBM) and brain metastases, continue to be an unmet medical challenge. Despite advances in cancer diagnostics and therapeutics, tumor cell colonization in the central nervous system renders most treatment options ineffective. This is primarily due to the selective permeability of the blood-brain barrier (BBB), which hinders the crossing of targeting agents into the brain. As such, repositioning medications that demonstrate anticancer effects and possess the ability to cross the BBB can be a promising option. Antidepressants, which are BBB-permeable, have been reported to exhibit cytotoxicity against tumor cells. Autophagy, specifically, has been identified as one of the common key mediators of antidepressant's antitumor effects. In this work, we provide a comprehensive overview of US Food and Drug Administration (FDA)-approved antidepressants with reported cytotoxic activities in different tumor models, where autophagy dysregulation was demonstrated to play the main part. As such, imipramine, maprotiline, fluoxetine and escitalopram were shown to induce autophagy, whereas nortriptyline, clomipramine and paroxetine were identified as autophagy inhibitors. Sertraline and desipramine, depending on the neoplastic context, were demonstrated to either induce or inhibit autophagy. Collectively, these medications were associated with favorable therapeutic outcomes in a variety of cancer cell models, including brain tumors.
Insights
Certain antidepressants can effectively treat brain tumors by influencing autophagy, a key cellular process. This research reviews FDA-approved antidepressants with anticancer effects, offering new therapeutic avenues for brain cancer patients.
Area of Science:
- Neuro-oncology
- Pharmacology
- Molecular Biology
Background:
- Malignant brain tumors like glioblastoma multiforme (GBM) and brain metastases present significant treatment challenges due to the blood-brain barrier (BBB).
- The BBB restricts the efficacy of many conventional cancer therapeutics.
- Repurposing existing medications that cross the BBB and possess anticancer properties is a promising strategy.
Purpose of the Study:
- To review FDA-approved antidepressants with demonstrated cytotoxic effects against tumor cells.
- To investigate the role of autophagy modulation as a mechanism for the antitumor activity of these antidepressants.
- To identify specific antidepressants that induce or inhibit autophagy in various cancer models.
Main Methods:
- Comprehensive literature review of studies reporting on FDA-approved antidepressants and their effects on cancer cells.
- Analysis of research focusing on the involvement of autophagy in mediating the anticancer effects of antidepressants.
- Categorization of antidepressants based on their observed impact on autophagy (induction or inhibition).
Main Results:
- Several FDA-approved antidepressants exhibit cytotoxicity against diverse tumor models, including brain tumors.
- Autophagy dysregulation is a central mechanism underlying the antitumor effects of these antidepressants.
- Specific antidepressants like imipramine, maprotiline, fluoxetine, and escitalopram were identified as autophagy inducers, while others like nortriptyline, clomipramine, and paroxetine were inhibitors. Sertraline and desipramine showed context-dependent effects.
Conclusions:
- FDA-approved antidepressants represent a viable class of drugs for repositioning in cancer therapy, particularly for brain tumors.
- Modulation of autophagy by antidepressants is a key factor in their observed anticancer efficacy.
- Further research into these BBB-permeable agents could lead to novel therapeutic strategies for central nervous system malignancies.
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