• amitriptyline
• antidepressant
• apoptosis
• autophagy
• cell proliferation
• cytotoxicity
• neuroblastoma

• Humans
• Amitriptyline/pharmacology
• Autophagy/drug effects
• Cell Proliferation/drug effects
• Neuroblastoma/metabolism
• Neuroblastoma/drug therapy
• Neuroblastoma/pathology
• Cell Line, Tumor
• Cell Survival/drug effects
• Antidepressive Agents, Tricyclic/pharmacology
• Antidepressive Agents/pharmacology
• Apoptosis/drug effects

• Bibliometric analysis
• Colorectal cancer
• Cytokines
• Depression
• Drugs
• Mechanism

• Caspase
• Desmethylclomipramine
• Epithelial mesenchymal transition
• TGF-β
• tBid

• Animals
• Humans
• Mice
• A549 Cells
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Death/drug effects
• Epithelial-Mesenchymal Transition/drug effects
• Glycogen Synthase Kinase 3 beta/metabolism
• Lung Neoplasms/drug therapy
• Lung Neoplasms/pathology
• Lung Neoplasms/metabolism
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria/drug effects
• Mitochondria/metabolism
• Myeloid Cell Leukemia Sequence 1 Protein/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• Transforming Growth Factor beta/metabolism
• Transforming Growth Factor beta1/metabolism
• Xenograft Model Antitumor Assays

• Apoptosis
• DNA fragmentation
• Hepatotoxicity
• Liver injury
• Oxidative stress
• SSRIs

• Rats
• Animals
• Antioxidants/pharmacology
• Rutin/pharmacology
• Vortioxetine
• Inflammation/drug therapy
• Glutathione/metabolism
• Chemical and Drug Induced Liver Injury/drug therapy
• Chemical and Drug Induced Liver Injury/prevention & control
• Biomarkers

• Egyptian Drug Authority

• PI3K-Akt-mTOR pathway
• apoptosis
• autophagy
• combination therapy
• paroxetine
• triple-negative breast cancer (TNBC)

• No. 2023SCUH0071 This study received funding from the Support Program of Innovation Research Project from 0 to 1
• No. 2023YFSY0046 the Support Program of the Science & Technology Department of Sichuan Provincial
• No. 2022YFS0061 Department of the Science and Technology of Sichuan Province

• antidepressants
• depression
• glioma
• overall survival

• National High Level Hospital Clinical Research
• National Natural Science Foundation of China
• CAMS Innovation Fund for Medical Sciences

• antidepressants
• drug repurposing
• glioma

• Humans
• Brain Neoplasms/drug therapy
• Antidepressive Agents/pharmacology
• Antidepressive Agents/therapeutic use
• Glioma/drug therapy
• Drug Repositioning
• Apoptosis/drug effects
• Glioblastoma/drug therapy
• Autophagy/drug effects
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use

• WNT/β-catenin signaling
• apoptosis
• drug repurposing
• glioblastoma
• temozolomide

• Drug Repositioning
• Apoptosis
• Glioma/drug therapy
• Glioma/pathology
• Xenograft Model Antitumor Assays
• Humans
• Animals
• Chloroquine/pharmacology
• Temozolomide/pharmacology
• Phloroglucinol/pharmacology
• Wnt Signaling Pathway/drug effects
• Cell Line, Tumor
• Male
• Rats
• Rats, Wistar
• Drug Therapy, Combination

• 5/13/21/2019/NCD-III Indian Council of Medical Research

• Artificial intelligence
• Combinatorial therapy
• Glioblastoma multiforme
• Nanotheranostic
• Organoid models
• Personalized medicine
• Therapeutic strategies

• Humans
• Glioblastoma/pathology
• Signal Transduction
• Tumor Microenvironment

• Amitriptyline
• Anticancer
• Apoptosis
• LDH
• Paroxetine

• 17-β estradiol
• Chronic stress
• Depression
• Neuroprotectants
• Resveratrol
• Rutin

• Antidepressants
• Cancer cells metabolism
• Cancer treatment
• Carcinostasis
• Molecular mechanisms

• Humans
• Depression/drug therapy
• Neoplasm Recurrence, Local/drug therapy
• Antidepressive Agents/pharmacology
• Antidepressive Agents/therapeutic use
• Tumor Microenvironment

• GBM
• Glioblastoma
• blood-brain barrier
• brain tumor
• drug repositioning
• non-cancer drugs

• Adult
• Humans
• Glioblastoma/drug therapy
• Glioblastoma/pathology
• Drug Repositioning
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Prognosis
• Brain Neoplasms/drug therapy
• Brain Neoplasms/pathology

In patients with gliomas, depression is a common complication that may cause severe psychological barriers and deteriorate the patient’s quality of life (QoL). Currently, the Hospital Anxiety and Depression Scale (HADS) is the most commonly used tool to diagnose depression in patients with gliomas. Female sex, unmarried status, low education level, high tumor grade, and a history of mental illness may increase the risks of depression and depressive symptoms in patients with gliomas. The QoL of patients with gliomas can be directly reduced by depression. Therefore, the evaluation and intervention of mood disorders could improve the overall QoL of patients with gliomas. Antidepressant use has become a treatment strategy for patients with gliomas and comorbid depression. This narrative review summarizes the current issues related to depression in patients with gliomas, including the prevalence, risk factors, and diagnostic criteria of depression as well as changes in QoL caused by comorbid depression and antidepressant use. The purpose of this review is to guide clinicians to assess the psychological status of patients with gliomas and to provide clinicians and oncologists with a new treatment strategy to improve the prognosis of such patients.

Tricyclic antidepressants (TCAs) are old and known therapeutic agents whose good safety profile makes them good candidates for drug repurposing. As the relevance of nerves in cancer development and progression is being unveiled, attention now turns to the use of nerve-targeting drugs, such as TCAs, as an interesting approach to combat cancer. In this review, we discuss current evidence about the safety of TCAs, their application to treat neuropathic pain in cancer patients, and in vitro and in vivo demonstrations of the antitumoral effects of TCAs. Finally, the results of ongoing clinical trials and future directions are discussed.

Growing evidence shows that nerves play an active role in cancer development and progression by altering crucial molecular pathways and cell functions. Conversely, the use of neurotropic drugs, such as tricyclic antidepressants (TCAs), may modulate these molecular signals with a therapeutic purpose based on a direct antitumoral effect and beyond the TCA use to treat neuropathic pain in oncology patients. In this review, we discuss the TCAs’ safety and their central effects against neuropathic pain in cancer, and the antitumoral effects of TCAs in in vitro and preclinical studies, as well as in the clinical setting. The current evidence points out that TCAs are safe and beneficial to treat neuropathic pain associated with cancer and chemotherapy, and they block different molecular pathways used by cancer cells from different locations for tumor growth and promotion. Likewise, ongoing clinical trials evaluating the antineoplastic effects of TCAs are discussed. TCAs are very biologically active compounds, and their repurposing as antitumoral drugs is a promising and straightforward approach to treat specific cancer subtypes and to further define their molecular targets, as well as an interesting starting point to design analogues with increased antitumoral activity.

• SSRIs
• antidepressants
• breast cancer
• oncological pharmacology
• stress
• tumor growth

• psychiatric disorders
• neuroscience

• Bipolar I disorder
• Bipolar II disorder
• Mitochondrial DNA copy number

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood–brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM.

• brain tumor
• drug delivery
• glioma
• repurposed drugs

•

Thirteen different neoplasms were shown to be susceptible to the antidepressant drug sertraline.

Sertraline hydrochloride is a first-line antidepressant with potential antineoplastic properties because of its structural similarity with other drugs capable to inhibit the translation-controlled tumor protein (TCTP), a biomolecule involved in cell proliferation. Recent studies suggest it could be repositioned for cancer treatment. In this review, we systematically map the findings that repurpose sertraline as an antitumoral agent, including the mechanisms of action that support this hypotesis. From experimental in vivo and in vitro tumor models of thirteen different types of neoplasms, three mechanisms of action are proposed: apoptosis, autophagy, and drug synergism. The antidepressant is able to inhibit TCTP, modulate chemotherapeutical resistance and exhibit proper cytotoxicity, resulting in reduced cell counting (in vitro) and shrunken tumor masses (in vivo). A mathematical equation determined possible doses to be used in human beings, supporting that sertraline could be explored in clinical trials as a TCTP-inhibitor.

• Antidepressant agents
• Apoptosis
• Drug repurposing
• Neoplasms
• Sertraline
• TCTP

Patients with malignant glioma often suffered from depression, which leads to an increased risk of detrimental outcomes. Imipramine, an FDA‐approved tricyclic antidepressant, has been commonly used to relieve depressive symptoms in the clinic. Recently, imipramine has been reported to participate in the suppression of tumour progression in several human cancers, including prostate cancer, colon cancer and lymphomas. However, the effect of imipramine on malignant glioma is largely unclear. Here, we show that imipramine significantly retarded proliferation of immortalized and primary glioma cells. Mechanistically, imipramine suppressed tumour proliferation by inhibiting yes‐associated protein (YAP), a recognized oncogene in glioma, independent of Hippo pathway. In addition to inhibiting YAP transcription, imipramine also promoted the subcellular translocation of YAP from nucleus into cytoplasm. Consistently, imipramine administration significantly reduced orthotopic tumour progression and prolonged survival of tumour‐bearing mice. Moreover, exogenous overexpression of YAP partially restored the inhibitory effect of imipramine on glioma progression. Most importantly, compared with imipramine or temozolomide (TMZ) monotherapy, combination therapy with imipramine and TMZ exhibited enhanced inhibitory effect on glioma growth both in vitro and in vivo, suggesting the synergism of both agents. In conclusion, we found that tricyclic antidepressant imipramine impedes glioma progression by inhibiting YAP. In addition, combination therapy with imipramine and TMZ may potentially serve as promising anti‐glioma regimens, thus predicting a broad prospect of clinical application.

• YAP
• glioma
• imipramine
• proliferation
• temozolomide

• Psychiatric agents
• anticancer activity
• chemosensitizers
• drug development
• in vitro tests
• in vivo studies

• bipolar disorder
• major depressive disorder
• mitochondrial dysfunction
• mood disorders
• novel therapies

Depression is a serious medical condition, typically treated by antidepressants. Conventional monotherapy can be effective only in 60–80% of patients, thus modern psychiatry deals with the challenge of new methods development. At the same moment, interactions between antidepressants and the occurrence of potential side effects raise serious concerns, which are even more exacerbated by the lack of relevant data on exact molecular mechanisms. Therefore, the aims of the study were to provide up-to-date information on the relative mechanisms of action of single antidepressants and their combinations. In this study, we evaluated the effect of single and combined antidepressants administration on mouse hippocampal neurons after 48 and 96 h in terms of cellular and biochemical features in vitro. We show for the first time that co-treatment with amitriptyline/imipramine + fluoxetine initiates in cells adaptation mechanisms which allow cells to adjust to stress and finally exerts less toxic events than in cells treated with single antidepressants. Antidepressants treatment induces in neuronal cells oxidative and nitrosative stress, which leads to micronuclei and double-strand DNA brakes formation. At this point, two different mechanistic events are initiated in cells treated with single and combined antidepressants. Single antidepressants (amitriptyline, imipramine or fluoxetine) activate cell cycle arrest resulting in proliferation inhibition. On the other hand, treatment with combined antidepressants (amitriptyline/imipramine + fluoxetine) initiates p16-dependent cell cycle arrest, overexpression of telomere maintenance proteins and finally restoration of proliferation. In conclusion, our findings may pave the way to better understanding of the stress-related effects on neurons associated with mono- and combined therapy with antidepressants.

• Amitriptyline
• Antidepressants
• Depression
• Fluoxetine
• Imipramine
• Neurons

• Antidepressant
• CRMP2
• Depression
• Fluoxetine
• Plasticity

We examined the effect of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on neuronal viability in mouse cortical near-pure neuronal cultures. Addition of fluoxetine to the media for 24 hours induced neuronal death in a concentration-dependent manner. To delineate the mechanisms of fluoxetine-induced neuronal death, we investigated the effects of trolox, cycloheximide (CHX), BDNF, z-VAD-FMK, and various metal-chelators on fluoxetine-induced neuronal death. Neuronal death was assessed by MTT assay. The addition of 20 µM fluoxetine to the media for 24 hours induced 60–70% neuronal death, which was associated with the hallmarks of apoptosis, chromatin condensation and DNA laddering. Fluoxetine-induced death was significantly attenuated by CHX, BDNF, or z-VAD-FMK. Treatment with antioxidants, trolox and ascorbate, also markedly attenuated fluoxetine-induced death. Interestingly, some divalent cation chelators (EGTA, Ca-EDTA, and Zn-EDTA) also markedly attenuated the neurotoxicity. Fluoxetine-induced reactive oxygen species (ROS) generation was measured using the fluorescent dye 2′,7′-dichlorofluorescin diacetate. Trolox and bathocuproine disulfonic acid (BCPS), a cell membrane impermeable copper ion chelator, markedly attenuated the ROS production and neuronal death. However, deferoxamine, an iron chelator, did not affect ROS generation or neurotoxicity. We examined the changes in intracellular copper concentration using a copper-selective fluorescent dye, Phen Green FL, which is quenched by free copper ions. Fluoxetine quenched the fluorescence in neuronal cells, and the quenching effect of fluoxetine was reversed by co-treatment with BCPS, however, not by deferoxamine. These findings demonstrate that fluoxetine could induce apoptotic and oxidative neuronal death associated with an influx of copper ions.

• Cell Death
• Copper
• Fluoxetine
• Neurons
• Reactive Oxygen Species

• amitriptyline
• antidepressants
• kidney
• paroxetine
• serotonin re-uptake inhibitors
• stereology
• tricyclics

• behavior
• mixture
• neurotoxicity
• oxidative stress
• psychiatric pharmaceutical

Glioblastoma is the most common and malignant primary brain tumour in adults, with a dismal prognosis. This is partly due to considerable inter- and intra-tumour heterogeneity. Changes in the cellular energy-producing mitochondrial respiratory chain complex (MRC) activities are a hallmark of glioblastoma relative to the normal brain, and associate with differential survival outcomes. Targeting MRC complexes with drugs can also facilitate anti-glioblastoma activity. Whether mutations in the mitochondrial DNA (mtDNA) that encode several components of the MRC contribute to these phenomena remains underexplored. We identified a germ-line mtDNA mutation (m. 14798T > C), enriched in glioblastoma relative to healthy controls, that causes an amino acid substitution F18L within the core mtDNA-encoded cytochrome b subunit of MRC complex III. F18L is predicted to alter corresponding complex III activity, and sensitivity to complex III-targeting drugs. This could in turn alter reactive oxygen species (ROS) production, cell behaviour and, consequently, patient outcomes. Here we show that, despite a heterogeneous mitochondrial background in adult glioblastoma patient biopsy-derived cell cultures, the F18L substitution associates with alterations in individual MRC complex activities, in particular a 75% increase in MRC complex II_III activity, and a 34% reduction in CoQ10, the natural substrate for MRC complex III, levels. Downstream characterisation of an F18L-carrier revealed an 87% increase in intra-cellular ROS, an altered cellular distribution of mitochondrial-specific ROS, and a 64% increased sensitivity to clomipramine, a repurposed MRC complex III-targeting drug. In patients, F18L-carriers that received the current standard of care treatment had a poorer prognosis than non-carriers (373 days vs. 415 days, respectively). Single germ-line mitochondrial mutations could predispose individuals to differential prognoses, and sensitivity to mitochondrial targeted drugs. Thus, F18L, which is present in blood could serve as a useful non-invasive biomarker for the stratification of patients into prognostically relevant groups, one of which requires a lower dose of clomipramine to achieve clinical effect, thus minimising side-effects.

• CoQ10
• OXPHOS
• ROS
• clomipramine
• glioblastoma
• mitochondria
• mtDNA
• mutation
• prognosis

• Clomipramine/pharmacology
• DNA, Mitochondrial/genetics
• Germ-Line Mutation/genetics
• Glioblastoma/genetics
• Humans
• Kaplan-Meier Estimate
• Male
• Mitochondria/metabolism
• Mutation/genetics
• Oxidation-Reduction
• Reactive Oxygen Species/metabolism
• Ubiquinone/analogs & derivatives
• Ubiquinone/metabolism

• Animals
• Cell Proliferation/drug effects
• Humans
• Ligands
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Receptors, Dopamine D2/agonists
• Receptors, Dopamine D2/metabolism
• Signal Transduction/drug effects

• T32 CA060395 NCI NIH HHS

• Nerve growth factor
• Neurite outgrowth
• PC12 cells
• Selective serotonin reuptake inhibitor
• Sertraline
• Sigma-1 receptor

• Animals
• Cell Survival/drug effects
• Fluvoxamine/pharmacology
• Mice
• Nerve Growth Factor/pharmacology
• Neuronal Outgrowth/drug effects
• PC12 Cells
• Rats
• Receptors, sigma/metabolism
• Sertraline/pharmacology
• Signal Transduction/drug effects
• Sigma-1 Receptor

Despite numerous advancements in the last decade, human gliomas such as astrocytoma and glioblastoma multiforme have the worst prognoses among all cancers. Anti-psychotic drugs are commonly prescribed to treat mental disorders among cancer patients, and growing empirical evidence has revealed their antitumor, anti-metastatic, anti-angiogenic, anti-proliferative, chemo-preventive, and neo-adjuvant efficacies in various in vitro, in vivo, and clinical glioma models. Anti-psychotic drugs have drawn the attention of physicians and researchers owing to their beneficial effects in the prevention and treatment of gliomas. This review highlights data on the therapeutic potential of various anti-psychotic drugs as anti-proliferative, chemopreventive, and anti-angiogenic agents in various glioma models via the modulation of upstream and downstream molecular targets involved in apoptosis, autophagy, oxidative stress, inflammation, and the cell cycle in in vitro and in vivo preclinical and clinical stages among glioma patients. The ability of anti-psychotic drugs to modulate various signaling pathways and multidrug resistance-conferring proteins that enhance the efficacy of chemotherapeutic drugs with low side-effects exemplifies their great potential as neo-adjuvants and potential chemotherapeutics in single or multimodal treatment approach. Moreover, anti-psychotic drugs confer the ability to induce glioma into oligodendrocyte-like cells and neuronal-like phenotype cells with reversal of epigenetic alterations through inhibition of histone deacetylase further rationalize their use in glioma treatment. The improved understanding of anti-psychotic drugs as potential chemotherapeutic drugs or as neo-adjuvants will provide better information for their use globally as affordable, well-tolerated, and effective anticancer agents for human glioma.

• anti-psychotic drugs
• atypical anti-psychotic
• glioma
• typical anti-psychotic
• valproic acid

• drug discovery
• drug repositioning
• drug targets
• molecular interactions
• orphan disease

• Computational Biology
• Disease
• Drug Discovery
• Drug Repositioning
• Genetics, Population
• Humans
• Proteins/metabolism
• Systems Biology/methods

• FKBP51
• antidepressants
• autophagy
• cancer
• depression

• Aging/drug effects
• Animals
• Antidepressive Agents/adverse effects
• Antidepressive Agents/therapeutic use
• Autophagy/drug effects
• Communicable Diseases/drug therapy
• Depression/drug therapy
• Disease Models, Animal
• Humans
• Inflammation/drug therapy
• Neoplasms/drug therapy
• Neurodegenerative Diseases/drug therapy

Depression is more common in women with breast cancer than the general population. Selective serotonin reuptake inhibitors (SSRIs), a group of antidepressants, are widely used for the treatment of patients with depression and a range of anxiety-related disorders. The association between the use of antidepressant medication and breast cancer is controversial. In this study, we investigated whether and how SSRIs induce the death of human breast cancer MCF-7 cells. Of the antidepressants tested in this study (amitriptyline, bupropion, fluoxetine, paroxetine, and tianeptine), paroxetine most reduced the viability of MCF-7 cells in a time-and dose-dependent manner. The exposure of MCF-7 cells to paroxetine resulted in mitochondrion-mediated apoptosis, which is assessed by increase in the number of cells with sub-G1 DNA content, caspase-8/9 activation, poly (ADP-ribose) polymerase cleavage, and Bax/Bcl-2 ratio and a reduction in the mitochondrial membrane potential. Paroxetine increased a generation of reactive oxygen species (ROS), intracellular Ca²⁺ levels, and p38 MAPK activation. The paroxetine-induced apoptotic events were reduced by ROS scavengers and p38 MAPK inhibitor, and the paroxetine’s effect was dependent on extracellular Ca²⁺ level. Paroxetine also showed a synergistic effect on cell death induced by chemotherapeutic drugs in MCF-7 and MDA-MB-231 cells. Our results showed that paroxetine induced apoptosis of human breast cancer MCF-7 cells through extracellular Ca²⁺-and p38 MAPK-dependent ROS generation. These results suggest that paroxetine may serve as an anticancer adjuvant to current cancer therapies for breast cancer patients with or without depression.

• MAPK
• apoptosis
• breast cancer
• calcium
• depression
• paroxetine
• reactive oxygen species