The antidepressant imipramine inhibits breast cancer growth by targeting estrogen receptor signaling and DNA repair events
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA788513 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17224909.fastq.gz | Fastqsanger.gz | |||
| SRR17224910.fastq.gz | Fastqsanger.gz | |||
| SRR17224911.fastq.gz | Fastqsanger.gz | |||
| SRR17224912.fastq.gz | Fastqsanger.gz | |||
| SRR17224913.fastq.gz | Fastqsanger.gz |
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Project description:Breast cancer is the most common cancer in women and the leading cause of cancer-related deaths in women worldwide. Although survival of breast cancer patients has improved in the last decade, major hurdles remain. Two problems associated with current therapies include acquired resistance and the debilitating side effects of treatment, especially chemotherapy. Therefore, safer treatment options that effectively suppress cancer progression and reduce treatment-associated side effects are much needed. Repurposing of clinically approved or investigational drugs could be one type of effective and safe options for treating cancer patients. Imipramine is a tricyclic antidepressant commonly used for many decades. It is a selective serotonin reuptake inhibitor (SSRI) and inhibits other neurotransmitters. Here, we report that imipramine blocks ER+ and TNBC growth and progression by inhibiting key proteins involved in ER-a signaling, cell cycle progression, and DNA repair and replication. Furthermore, imipramine improved the efficacy of PARP inhibitor therapy in TNBC. This study is the first to show that imipramine is a promising therapeutic option for breast cancer and to define imipramine’s mechanism of action and targets in breast cancer. This pre-clinical study is the basis for a currently ongoing clinical trial testing the efficacy of imipramine for treating breast cancer.
2023-07-06 | GSE190814 | GEO
Project description:Aberrant activities of various cell cycle and DNA repair proteins promote cancer growth and progression and render them resistant to therapies. Here, we demonstrate that the anti-depressant imipramine blocks growth of triple-negative (TNBC) and estrogen receptor-positive (ER+) breast cancers by inducing cell cycle arrest and by blocking heightened homologous recombination (HR) and non-homologous end joining-mediated (NHEJ) DNA repair activities. Our results reveal that imipramine inhibits the expression of several cell cycle- and DNA repair-associated proteins including E2F1, CDK1, Cyclin D1, and RAD51. In addition, we show that imipramine inhibits the growth of ER + breast cancers by inhibiting the estrogen receptor- α (ER-α) signaling. Our studies in preclinical mouse models and ex vivo explants from breast cancer patients show that imipramine sensitizes TNBC to the PARP inhibitor olaparib and endocrine resistant ER + breast cancer to anti-estrogens. Our studies suggest that repurposing imipramine could enhance routine care for breast cancer patients. Based on these results, we designed an ongoing clinical trial, where we are testing the efficacy of imipramine for treating patients with triple-negative and estrogen receptor-positive breast cancer. Since aberrant DNA repair activity is used by many cancers to survive and become resistant to therapy, imipramine could be used alone and/or with currently used drugs for treating many aggressive cancers.
| S-EPMC10313451 | biostudies-literature
Project description:Background: Examining transcriptional regulation by existing antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Further, given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods: We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine (14 daily injections), and a rapidly acting, experimental, non-monoamine-based antidepressant, ketamine (single injection), in mice subjected to chronic social defeat stress, a validated model of depression, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results: We identified approximately equal numbers of responder and non-responder mice following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus than other brain regions; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in ketamine and imipramine responders were most similar in PFC, where the least transcriptional regulation occurred for each drug. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptible associated transcriptional changes as well as induced resilient associated transcription in PFC, with effects varying by drug and brain region studied. Conclusions: We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility and inducing resilience associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine. mRNA profiles of susceptibility to chronic social defeat stress as well as treatment response were generated across 4 separate brain regions, with a sample size of 3-5 per group.
2016-07-27 | E-GEOD-81672 | biostudies-arrayexpress
Project description:Background: Examining transcriptional regulation by existing antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Further, given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods: We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine (14 daily injections), and a rapidly acting, experimental, non-monoamine-based antidepressant, ketamine (single injection), in mice subjected to chronic social defeat stress, a validated model of depression, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results: We identified approximately equal numbers of responder and non-responder mice following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus than other brain regions; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in ketamine and imipramine responders were most similar in PFC, where the least transcriptional regulation occurred for each drug. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptible associated transcriptional changes as well as induced resilient associated transcription in PFC, with effects varying by drug and brain region studied. Conclusions: We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility and inducing resilience associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine.
2016-07-27 | GSE81672 | GEO
Project description:It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N=424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is also downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behaviour, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC was is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists had antidepressant-like effects and up-regulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.
2020-03-31 | GSE146446 | GEO
Project description:Estrogen Promotes Mandibular Condylar Fibrocartilage Chondrogenesis and Inhibits Degeneration Via Estrogen Receptor Alpha in Female Mice
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Project description:Glial cells (microglia and astrocytes) have recently became appreciated as an important target for antidepressant drugs. Here we report on the results of comprehensive proteomic analysis of the alteration in protein profile of rat primary mixed glial culture exposed to imipramine. Two-dimensional differential in gel electrophoresis method allowed to identify 62 proteins regulated by imipramine hydrochloride. Functional analysis revealed the impact of imipramine on the level of proteins involved in oxidative stress. Imipramine upregulated proteins related to glycolysis but downregulated many mitochondrial proteins also enzymes of oxidative phosphorylation. Moreover, imipramine influenced the proteins engaged in phagocytosis and cell migration. Alteration in the level of large number of structural and plasma membrane associated proteins evidenced a widespread cytoskeleton and membrane rearrangement. Imipramine triggered decrease of mitochondrial membrane potential, impairment of protein synthesis and downregulation of chaperon proteins, what could be related to increased apoptosis. Many imipramine regulated proteins, among them chaperons, cathepsins and annexins are evidenced to be engaged in immunity response. Overall these experimental findings suggest that in response to imipramine, glial cells (mainly microglia) undergo a transition toward more quiescent, metabolically less demanding phenotype.
2018-05-17 | PXD007977 | Pride
Project description:To investigate the molecular mechanisms by which estrogen receptor α (ERα) inhibits type I IFN-induced signaling. We identified genes induced by ERα signaling using data obtained from RNA-seq of MCF7 cells treated or untreated with selective ERα agonist propyl pyrazole triol (PPT).
2022-05-18 | GSE203058 | GEO
Project description:Genetic determinants of antidepressant response
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Project description:Genetic determinants of antidepressant response
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