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Adornetto A, Laganà ML, Satriano A, Licastro E, Corasaniti MT, Bagetta G, Russo R. The Antidepressant Drug Amitriptyline Affects Human SH-SY5Y Neuroblastoma Cell Proliferation and Modulates Autophagy. Int J Mol Sci 2024; 25:10415. [PMID: 39408742 PMCID: PMC11476963 DOI: 10.3390/ijms251910415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/20/2024] [Accepted: 09/23/2024] [Indexed: 10/20/2024] Open
Abstract
Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and is prescribed off-label for several neurological conditions like neuropathic pain, migraines and anxiety. Besides their action on the reuptake of monoaminergic neurotransmitters, tricyclic antidepressants interact with several additional targets that may contribute to either therapeutic or adverse effects. Here, we investigated the effects of amitriptyline on proliferation and autophagy (i.e., an evolutionarily conserved catabolic pathway responsible for the degradation and recycling of cytoplasmic material) in human SH-SY5Y neuroblastoma cell cultures. The dose and time-dependent upregulation of the autophagy marker LC3II and the autophagy receptor p62, with the accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to the amitriptyline. These effects were accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5-/- MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine, suggesting that they were independent from autophagy modulation. Our findings demonstrate that amitriptyline acts on pathways crucial for cell and tissue homeostasis (i.e., autophagy and proliferation) and pose the basis for further studies on the potential therapeutic application of amitriptyline, as well as the consequences of its use for long-term treatments.
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Affiliation(s)
- Annagrazia Adornetto
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (A.A.); (G.B.)
| | - Maria Luisa Laganà
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (A.A.); (G.B.)
| | - Andrea Satriano
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (A.A.); (G.B.)
| | - Ester Licastro
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (A.A.); (G.B.)
| | - Maria Tiziana Corasaniti
- School of Hospital Pharmacy, Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy;
| | - Giacinto Bagetta
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (A.A.); (G.B.)
| | - Rossella Russo
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (A.A.); (G.B.)
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Zhu C, Lu Y, Wang S, Song J, Ding Y, Wang Y, Dong C, Liu J, Qiu W, Qi W. Nortriptyline hydrochloride, a potential candidate for drug repurposing, inhibits gastric cancer by inducing oxidative stress by triggering the Keap1-Nrf2 pathway. Sci Rep 2024; 14:6050. [PMID: 38480798 PMCID: PMC10937941 DOI: 10.1038/s41598-024-56431-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 03/06/2024] [Indexed: 03/17/2024] Open
Abstract
Effective drugs for the treatment of gastric cancer (GC) are still lacking. Nortriptyline Hydrochloride (NTP), a commonly used antidepressant medication, has been demonstrated by numerous studies to have antitumor effects. This study first validated the ability of NTP to inhibit GC and preliminarily explored its underlying mechanism. To begin with, NTP inhibits the activity of AGS and HGC27 cells (Human-derived GC cells) in a dose-dependent manner, as well as proliferation, cell cycle, and migration. Moreover, NTP induces cell apoptosis by upregulating BAX, BAD, and c-PARP and downregulating PARP and Bcl-2 expression. Furthermore, the mechanism of cell death caused by NTP is closely related to oxidative stress. NTP increases intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreasing the mitochondrial membrane potential (MMP) and inducing glucose (GSH) consumption. While the death of GC cells can be partially rescued by ROS inhibitor N-acetylcysteine (NAC). Mechanistically, NTP activates the Kelch-like ECH-associated protein (Keap1)-NF-E2-related factor 2 (Nrf2) pathway, which is an important pathway involved in oxidative stress. RNA sequencing and proteomics analysis further revealed molecular changes at the mRNA and protein levels and provided potential targets and pathways through differential gene expression analysis. In addition, NTP can inhibited tumor growth in nude mouse subcutaneous tumor models constructed respectively using AGS and MFC (mouse-derived GC cells), providing preliminary evidence of its effectiveness in vivo. In conclusion, our study demonstrated that NTP exhibits significant anti-GC activity and is anticipated to be a candidate for drug repurposing.
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Affiliation(s)
- Chunyang Zhu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yangyang Lu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shasha Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jialin Song
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yixin Ding
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yan Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chen Dong
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jiani Liu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wensheng Qiu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Weiwei Qi
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
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Sertraline inhibits stress-induced tumor growth through regulating CD8+ T cell-mediated anti-tumor immunity. Anticancer Drugs 2022; 33:935-942. [PMID: 36066403 DOI: 10.1097/cad.0000000000001383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Chronic stress has been reported to be associated with tumor initiation and progression. But the underlying mechanism and the specific role of tumor immunity in this process are still unknown. Herein, we applied the repeated restrain stress model in C57BL/6J mice and found that the tumor growth in stressed mice was accelerated compared with that in control mice. In addition, serotonin, also called 5-hydroxytryptamine (5-HT), in the serum of stressed mice was also elevated. Sertraline, a selective serotonin reuptake inhibitor used in the clinic, can restore the serum 5-HT level in stressed mice and restrain tumor growth. We further explored the distribution of major immune cells, including B lymphocytes cells, T lymphocytes, natural killer cells, dendritic cells, tumor-associated macrophages (TAM) and regulatory T cells (Treg). We found that the infiltration of CD8+ T cells in the tumor microenvironment (TME) decreased significantly in stressed mice. And the extra 5-HT treatment could further decrease the infiltration of CD8+ T cells in the TME. The expression of IFN-γ and Granular enzyme B (GzmB) in CD8+ T cells were also dropped in the stressed mice group, whereas the expression of programmed cell death protein 1 (PD-1) on CD8+ T cells was increased. The T cell deficiency induced by stress can be reversed by sertraline, indicating its promising role in strengthening the efficacy of anti-PDL1/PD-1 immunotherapy. The present study provides new mechanistic insights into the impact of chronic stress on antitumor immunity and implicates a novel combined immunotherapy strategy for cancer patients with chronic stress.
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Petrosyan E, Fares J, Cordero A, Rashidi A, Arrieta VA, Kanojia D, Lesniak MS. Repurposing autophagy regulators in brain tumors. Int J Cancer 2022; 151:167-180. [PMID: 35179776 PMCID: PMC9133056 DOI: 10.1002/ijc.33965] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/25/2022] [Accepted: 01/31/2022] [Indexed: 11/09/2022]
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.
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Affiliation(s)
- Edgar Petrosyan
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Jawad Fares
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Alex Cordero
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Aida Rashidi
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Víctor A. Arrieta
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Deepak Kanojia
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Maciej S Lesniak
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
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Asensi-Cantó A, López-Abellán MD, Castillo-Guardiola V, Hurtado AM, Martínez-Penella M, Luengo-Gil G, Conesa-Zamora P. Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment. Cancers (Basel) 2022; 14:cancers14133248. [PMID: 35805019 PMCID: PMC9265090 DOI: 10.3390/cancers14133248] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/26/2022] [Accepted: 06/28/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary 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. Abstract 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.
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Affiliation(s)
- Antonio Asensi-Cantó
- Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), 30107 Guadalupe, Spain; (A.A.-C.); (M.D.L.-A.); (M.M.-P.)
- Servicio de Farmacia Hospitalaria, Hospital Universitario Santa Lucía, 30202 Cartagena, Spain
- Grupo de Investigación en Patología Molecular y Farmacogenética, Servicios de Anatomía Patológica y Análisis Clínicos, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Universitario Santa Lucía, 30202 Cartagena, Spain; (V.C.-G.); (A.M.H.)
| | - María Dolores López-Abellán
- Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), 30107 Guadalupe, Spain; (A.A.-C.); (M.D.L.-A.); (M.M.-P.)
- Grupo de Investigación en Patología Molecular y Farmacogenética, Servicios de Anatomía Patológica y Análisis Clínicos, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Universitario Santa Lucía, 30202 Cartagena, Spain; (V.C.-G.); (A.M.H.)
| | - Verónica Castillo-Guardiola
- Grupo de Investigación en Patología Molecular y Farmacogenética, Servicios de Anatomía Patológica y Análisis Clínicos, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Universitario Santa Lucía, 30202 Cartagena, Spain; (V.C.-G.); (A.M.H.)
| | - Ana María Hurtado
- Grupo de Investigación en Patología Molecular y Farmacogenética, Servicios de Anatomía Patológica y Análisis Clínicos, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Universitario Santa Lucía, 30202 Cartagena, Spain; (V.C.-G.); (A.M.H.)
- Grupo de Investigación en Inmunobiología para la Acuicultura, Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain
| | - Mónica Martínez-Penella
- Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), 30107 Guadalupe, Spain; (A.A.-C.); (M.D.L.-A.); (M.M.-P.)
- Servicio de Farmacia Hospitalaria, Hospital Universitario Santa Lucía, 30202 Cartagena, Spain
| | - Ginés Luengo-Gil
- Grupo de Investigación en Patología Molecular y Farmacogenética, Servicios de Anatomía Patológica y Análisis Clínicos, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Universitario Santa Lucía, 30202 Cartagena, Spain; (V.C.-G.); (A.M.H.)
- Correspondence: (G.L.-G.); (P.C.-Z.); Tel.: +34-968-128-600 (ext. 951615) (G.L.-G. & P.C.-Z.)
| | - Pablo Conesa-Zamora
- Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), 30107 Guadalupe, Spain; (A.A.-C.); (M.D.L.-A.); (M.M.-P.)
- Grupo de Investigación en Patología Molecular y Farmacogenética, Servicios de Anatomía Patológica y Análisis Clínicos, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Universitario Santa Lucía, 30202 Cartagena, Spain; (V.C.-G.); (A.M.H.)
- Correspondence: (G.L.-G.); (P.C.-Z.); Tel.: +34-968-128-600 (ext. 951615) (G.L.-G. & P.C.-Z.)
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Sołek P, Mytych J, Tabęcka-Łonczyńska A, Koziorowski M. Molecular Consequences of Depression Treatment: A Potential In Vitro Mechanism for Antidepressants-Induced Reprotoxic Side Effects. Int J Mol Sci 2021; 22:11855. [PMID: 34769286 PMCID: PMC8584852 DOI: 10.3390/ijms222111855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 10/24/2021] [Accepted: 10/30/2021] [Indexed: 11/16/2022] Open
Abstract
The incidence of depression among humans is growing worldwide, and so is the use of antidepressants. However, our fundamental understanding regarding the mechanisms by which these drugs function and their off-target effects against human sexuality remains poorly defined. The present study aimed to determine their differential toxicity on mouse spermatogenic cells and provide mechanistic data of cell-specific response to antidepressant and neuroleptic drug treatment. To directly test reprotoxicity, the spermatogenic cells (GC-1 spg and GC-2 spd cells) were incubated for 48 and 96 h with amitriptyline (hydrochloride) (AMI), escitalopram (ESC), fluoxetine (hydrochloride) (FLU), imipramine (hydrochloride) (IMI), mirtazapine (MIR), olanzapine (OLZ), reboxetine (mesylate) (REB), and venlafaxine (hydrochloride) (VEN), and several cellular and biochemical features were assessed. Obtained results reveal that all investigated substances showed considerable reprotoxic potency leading to micronuclei formation, which, in turn, resulted in upregulation of telomeric binding factor (TRF1/TRF2) protein expression. The TRF-based response was strictly dependent on p53/p21 signaling and was followed by irreversible G2/M cell cycle arrest and finally initiation of apoptotic cell death. In conclusion, our findings suggest that antidepressants promote a telomere-focused DNA damage response in germ cell lines, which broadens the established view of antidepressants' and neuroleptic drugs' toxicity and points to the need for further research in this topic with the use of in vivo models and human samples.
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Affiliation(s)
- Przemysław Sołek
- Department of Biotechnology, Institute of Biology and Biotechnology, University of Rzeszow, Werynia 2, 36-100 Kolbuszowa, Poland; (A.T.-Ł.); (M.K.)
| | - Jennifer Mytych
- Department of Biotechnology, Institute of Biology and Biotechnology, University of Rzeszow, Werynia 2, 36-100 Kolbuszowa, Poland; (A.T.-Ł.); (M.K.)
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Shih WT, Yang PR, Chen KJ, Yang YH, Lu ML, Chen VCH, Shen YC. Antidepressants use is associated with overall survival improvement of patients with gastric cancer after surgery and adjuvant chemotherapy in Taiwan: A large population-based cohort study. Medicine (Baltimore) 2021; 100:e27031. [PMID: 34449480 PMCID: PMC8389936 DOI: 10.1097/md.0000000000027031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 08/07/2021] [Indexed: 01/04/2023] Open
Abstract
To determine whether exposure to antidepressants (ATDs) results in improved overall survival (OS) of patients with gastric cancer (GC) after surgery, we conducted a large cohort study and considered confounding factors that might affect the research outcomes.Patients who received a new diagnosis of GC and received surgery and chemotherapy between 1999 and 2008 were recruited and were classified into different groups based on the ATD level used. The association between the OS of patients with GC after surgery with different levels of ATD use, and the hazard ratio with comorbidities at different ATD use levels were compared.According to Kaplan-Meier method, the more of an ATD was taken, the longer the OS and a dose-dependent relationship was discovered in the OS curve; the adjusted HRs were 0.76 (95% confidence interval [CI] = 0.68-0.84) and 0.48 (95% CI = 0.41-0.57) for ATD users taking a cumulative defined daily dose (cDDD) of 28-167 and ≧168, respectively. Sensitivity analyzes were performed to investigate the effect of various comorbidities on OS with different degrees of ATD use and the results remained consistent among the varying models. Additionally, the effect of ATD use still exhibited a dose-dependent relationship in distinct stratifications for sex and age.The OS for patients with GC after surgery and chemotherapy improved with ATD use, and a dose-dependent relationship was discovered in this study. Further studies on the association between OS of GC and ATD use are required.
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Affiliation(s)
- Wei-Tai Shih
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Pei-Rung Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
- School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ko-Jung Chen
- Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yao-Hsu Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
- School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan
- Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Mong-Liang Lu
- Department of Psychiatry, Wan-Fang Hospital and School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Vincent Chin-Hung Chen
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Psychiatry, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yi-Chia Shen
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
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Dang S, Kumari P. Anti-cancer potential of some commonly used drugs. Curr Pharm Des 2021; 27:4530-4538. [PMID: 34161206 DOI: 10.2174/1381612827666210622104821] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 05/18/2021] [Indexed: 12/24/2022]
Abstract
Cancer is a global concern leading to millions of deaths every year. A declining trend in new drug discovery and development is becoming one of the major issues among the pharmaceutical, biotechnology industries, and regulatory agencies. New drug development is proven to be a very lengthy and costly process. The launch of a new drug takes 8-12 years and huge investments. The success rate in oncology therapeutics is also low due to toxicities at the pre-clinical and clinical trial levels. Many oncological drugs get rejected at a very promising stage, showing adverse reactions on healthy cells. Thus, exploring new therapeutic benefits of the existing, shelved drugs for their anti-cancerous action could result in a therapeutic approach preventing the toxicities which occur during clinical trials. Drug repurposing has the potential to overcome the challenges faced via conventional way of drug discovery and is becoming an area of interest for researchers and scientists. However, very few in vivo studies are conducted to prove the anti-cancerous activity of the drugs. Insufficient in vivo animal studies and a lack of human clinical trials are the lacunae in the field of drug repurposing. This review focuses on an aspect of drug repurposing for cancer therapeutics. Various studies that show that drugs approved for clinical indications other than cancer have shown promising anti-cancer activities. Some of the commonly used drugs like Benzodiazepines (Diazepam, Midzolam), Antidepressants (Imipramine, Clomipramine, and Citalopram), Antiepileptic (Valporic acid, Phenytoin), Antidiabetics (metformin), etc. have been reported to show potential activity against the cancerous cells.
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Affiliation(s)
- Shweta Dang
- Department of Biotechnology, Jaypee Institute of Information Technology, NOIDA, U.P, India
| | - Pallavi Kumari
- Department of Biotechnology, Jaypee Institute of Information Technology, NOIDA, U.P, India
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Brodnanova M, Hatokova Z, Evinova A, Cibulka M, Racay P. Differential impact of imipramine on thapsigargin- and tunicamycin-induced endoplasmic reticulum stress and mitochondrial dysfunction in neuroblastoma SH-SY5Y cells. Eur J Pharmacol 2021; 902:174073. [PMID: 33798597 DOI: 10.1016/j.ejphar.2021.174073] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 03/18/2021] [Accepted: 03/26/2021] [Indexed: 01/10/2023]
Abstract
The aim of our work was to study effect of antidepressant imipramine on both thapsigargin- and tunicamycin-induced ER stress and mitochondrial dysfunction in neuroblastoma SH-SY5Y cells. ER stress in SH-SY5Y cells was induced by either tunicamycin or thapsigargin in the presence or absence of imipramine. Cell viability was tested by the MTT assay. Splicing of XBP1 mRNA was studied by RT-PCR. Finally, expression of Hrd1 and Hsp60 was determined by Western blot analysis. Our findings provide evidence that at high concentrations imipramine potentiates ER stress-induced death of SH-SY5Y cells. The effect of imipramine on ER stress-induced death of SH-SY5Y cells was stronger in combination of imipramine with thapsigargin. In addition, we have found that treatment of SH-SY5Y cells with imipramine in combination of either thapsigargin or tunicamycin is associated with the alteration of ER stress-induced IRE1α-XBP1 signalling. Despite potentiation of ER stress-induced XBP1 splicing, imipramine suppresses both thapsigargin- and tunicamycin-induced expression of Hrd1. Finally, imipramine in combination with thapsigargin, but not tunicamycin, aggravates ER stress-induced mitochondrial dysfunction without significant impact on intracellular mitochondrial content as indicated by the unaltered expression of Hsp60. Our results indicate the possibility that chronic treatment with imipramine might be associated with a higher risk of development and progression of neurodegenerative disorders, in particular those allied with ER stress and mitochondrial dysfunction like Parkinson's and Alzheimer's disease.
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Affiliation(s)
- Maria Brodnanova
- Department of Medical Biochemistry, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Mala Hora 4D, SK-03601 Martin, Slovakia
| | | | | | | | - Peter Racay
- Department of Medical Biochemistry, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Mala Hora 4D, SK-03601 Martin, Slovakia.
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Giampieri R, Cantini L, Giglio E, Bittoni A, Lanese A, Crocetti S, Pecci F, Copparoni C, Meletani T, Lenci E, Lupi A, Baleani MG, Berardi R. Impact of Polypharmacy for Chronic Ailments in Colon Cancer Patients: A Review Focused on Drug Repurposing. Cancers (Basel) 2020; 12:2724. [PMID: 32977434 PMCID: PMC7598185 DOI: 10.3390/cancers12102724] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/15/2020] [Accepted: 09/21/2020] [Indexed: 01/10/2023] Open
Abstract
Colorectal cancer is characterized by high incidence worldwide. Despite increased awareness and early diagnosis thanks to screening programmes, mortality remains high, particularly for patients with metastatic involvement. Immune checkpoint inhibitors or poly (ADP-ribose) polymerase (PARP)-inhibitors have met with disappointing results when used in this setting, opposed to other malignancies. New drugs with different mechanisms of action are needed in this disease. Drug repurposing might offer new therapeutic options, as patients with metastatic colorectal cancer often share risk factors for other chronic diseases and thus frequently are on incidental therapy with these drugs. The aim of this review is to summarise the published results of the activity of drugs used to treat chronic medications in patients affected by colorectal cancer. We focused on antihypertensive drugs, Non-Steroid Anti-inflammatory Drugs (NSAIDs), metformin, antidepressants, statins and antibacterial antibiotics. Our review shows that there are promising results with beta blockers, statins and metformin, whereas data concerning antidepressants and antibacterial antibiotics seem to show a potentially harmful effect. It is hoped that further prospective trials that take into account the role of these drugs as anticancer medications are conducted.
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Affiliation(s)
- Riccardo Giampieri
- Division of Medical Oncology, University Hospital—Marche Polytechnic University, Ancona, 60126 Marche, Italy; (L.C.); (E.G.); (A.B.); (A.L.); (S.C.); (F.P.); (C.C.); (T.M.); (E.L.); (A.L.); (M.G.B.); (R.B.)
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11
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Integration of genetic variants and gene network for drug repurposing in colorectal cancer. Pharmacol Res 2020; 161:105203. [PMID: 32950641 DOI: 10.1016/j.phrs.2020.105203] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 08/27/2020] [Accepted: 09/09/2020] [Indexed: 12/14/2022]
Abstract
Even though many genetic risk loci for human diseases have been identified and comprehensively cataloged, strategies to guide clinical research by integrating the extensive results of genetic studies and biological resources are still limited. Moreover, integrative analyses that provide novel insights into disease biology are expected to be especially useful for drug discovery. Herein, we used text mining of genetic studies on colorectal cancer (CRC) and assigned biological annotations to identified risk genes in order to discover novel drug targets and potential drugs for repurposing. Risk genes for CRC were obtained from PubMed text mining, and for each gene, six functional and bioinformatic annotations were analyzed. The annotations include missense mutations, cis-expression quantitative trait loci (cis-eQTL), molecular pathway analyses, protein-protein interactions (PPIs), a genetic overlap with knockout mouse phenotypes, and primary immunodeficiency (PID). We then prioritized the biological risk candidate genes according to a scoring system of the six functional annotations. Each functional annotation was assigned one point, and those genes with a score ≥2 were designated "biological CRC risk genes". Using this method, we revealed 82 biological CRC risk genes, which were mapped to 128 genes in an expanded PPI network. Further utilizing DrugBank and the Therapeutic Target Database, we found 21 genes in our list that are targeted by 166 candidate drugs. Based on data from ClinicalTrials.gov and literature review, we found four known target genes with six drugs for clinical treatment in CRC, and three target genes with nine drugs supported by previous preclinical results in CRC. Additionally, 12 genes are targeted by 32 drugs approved for other indications, which can possibly be repurposed for CRC treatment. Finally, analysis from Connectivity Map (CMap) showed that 18 drugs have a high potential for CRC.
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12
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Capatina AL, Lagos D, Brackenbury WJ. Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges. Rev Physiol Biochem Pharmacol 2020; 183:1-43. [PMID: 32865696 DOI: 10.1007/112_2020_46] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ion channels are key regulators of cancer cell pathophysiology. They contribute to a variety of processes such as maintenance of cellular osmolarity and membrane potential, motility (via interactions with the cytoskeleton), invasion, signal transduction, transcriptional activity and cell cycle progression, leading to tumour progression and metastasis. Ion channels thus represent promising targets for cancer therapy. Ion channels are attractive targets because many of them are expressed at the plasma membrane and a broad range of existing inhibitors are already in clinical use for other indications. However, many of the ion channels identified in cancer cells are also active in healthy normal cells, so there is a risk that certain blockers may have off-target effects on normal physiological function. This review describes recent research advances into ion channel inhibitors as anticancer therapeutics. A growing body of evidence suggests that a range of existing and novel Na+, K+, Ca2+ and Cl- channel inhibitors may be effective for suppressing cancer cell proliferation, migration and invasion, as well as enhancing apoptosis, leading to suppression of tumour growth and metastasis, either alone or in combination with standard-of-care therapies. The majority of evidence to date is based on preclinical in vitro and in vivo studies, although there are several examples of ion channel-targeting strategies now reaching early phase clinical trials. Given the strong links between ion channel function and regulation of tumour growth, metastasis and chemotherapy resistance, it is likely that further work in this area will facilitate the development of new therapeutic approaches which will reach the clinic in the future.
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Affiliation(s)
| | - Dimitris Lagos
- Hull York Medical School, York, UK
- York Biomedical Research Institute, University of York, York, UK
| | - William J Brackenbury
- Department of Biology, University of York, York, UK.
- York Biomedical Research Institute, University of York, York, UK.
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13
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Avendaño-Félix M, Aguilar-Medina M, Bermudez M, Lizárraga-Verdugo E, López-Camarillo C, Ramos-Payán R. Refocusing the Use of Psychiatric Drugs for Treatment of Gastrointestinal Cancers. Front Oncol 2020; 10:1452. [PMID: 32923398 PMCID: PMC7456997 DOI: 10.3389/fonc.2020.01452] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 07/08/2020] [Indexed: 12/14/2022] Open
Abstract
Gastrointestinal cancers (GICs) are the most common human tumors worldwide. Treatments have limited effects, and increasing global cancer burden makes it necessary to investigate alternative strategies such as drug repurposing. Interestingly, it has been found that psychiatric drugs (PDs) are promising as a new generation of cancer chemotherapies due to their anti-neoplastic properties. This review compiles the state of the art about how PDs have been redirected for cancer therapeutics in GICs. PDs, especially anti-psychotics, anti-depressants and anti-epileptic drugs, have shown effects on cell viability, cell growth, inhibition of proliferation (cell cycle arrest), apoptosis promotion by caspases activation or cytochrome C release, production of reactive oxygen species (ROS) and nuclear fragmentation over esophageal, gastric, colorectal, liver and pancreatic cancers. Additionally, PDs can inhibit neovascularization, invasion and metastasis in a dose-dependent manner. Moreover, they can induce chemosensibilization to 5-fluorouracil and cisplatin and can act synergistically with anti-neoplastic drugs such as gemcitabine, paclitaxel and oxaliplatin. All anti-cancer activities are given by activation or inhibition of pathways such as HDAC1/PTEN/Akt, EGFR/ErbB2/ErbB3, and PI3K/Akt; PI3K-AK-mTOR, HDAC1/PTEN/Akt; Wnt/β-catenin. Further investigations and clinical trials are needed to elucidate all molecular mechanisms involved on anti-cancer activities as well as adverse effects on patients.
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Affiliation(s)
- Mariana Avendaño-Félix
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
| | - Maribel Aguilar-Medina
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
| | - Mercedes Bermudez
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
| | - Erik Lizárraga-Verdugo
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico
| | - Rosalío Ramos-Payán
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Mexico
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14
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Heterometrus Spinifer: An Untapped Source of Anti-Tumor Molecules. BIOLOGY 2020; 9:biology9070150. [PMID: 32630812 PMCID: PMC7408436 DOI: 10.3390/biology9070150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 12/11/2022]
Abstract
Despite intensive research, cancer incidence and mortality continue to rise. Consequently, the necessity to develop effective anti-cancer therapy is apparent. We have recently shown that the gut bacteria of animals living in polluted environments, such as crocodiles, are a potential source of novel anti-tumor molecules. To extend this work to other resilient species, we investigated the anti-tumor effects of gut bacteria of Heterometrus spinifer (a scorpion). Bacteria from the feces and gut were isolated, identified and evaluated for their anti-tumor effects. Bacterial-conditioned media was prepared in Roswell Park Memorial Institute (RPMI) 1640 media, and cytotoxicity and growth inhibitory properties were examined against cervical (HeLa) cancer cells. Liquid chromatography–mass spectrometry (LC-MS) was conducted to establish the identity of the molecules. Eighteen bacteria species from the gut (HSG01-18) and ten bacteria species from feces (HSF01-10) were tested for anti-tumor effects. Bacterial-conditioned media from scorpion gut and feces exhibited significant growth inhibitory effects against HeLa cells of 66.9% and 83.8%, respectively. Microscopic analysis of cancer cells treated with conditioned media HSG12 and HSG16 revealed apoptosis-like effects. HSG12 was identified as Pseudomonas aeruginosa and HSG16 was identified as Bacillus subtilis. Both conditioned media exhibited 100% growth inhibitory effects versus a selection of cancer cells, comprising cervical, breast and prostate cancer cells. LC–MS indicated the presence of 72 and 38 compounds, detected from HSG12 and HSG16, respectively. Out of these compounds, 47 were successfully identified while the remainder were unidentified and are possibly novel. This study suggests that the fecal and gut microbiota of scorpions might possess molecules with anti-cancer properties, however, further intensive research is needed to assess these expectations.
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15
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Chen L, Li X, Li C, Zou C. Antidepressant use and colorectal cancer morbidity and mortality: A dose-response meta analysis. Medicine (Baltimore) 2020; 99:e20185. [PMID: 32481383 DOI: 10.1097/md.0000000000020185] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The risk of colorectal cancer associated to antidepressant use remains unclear. The purpose of this meta-analysis was to investigate the risk of colorectal cancer associated to antidepressant use.Medline, Embase, Web of Science, and Cochrane Database were accessed from the dates of their establishment to October 2018, to collect study of antidepressant use and colorectal cancer morbidity and mortality. Then a meta-analysis was conducted using Stata 12.0 software.A total of 11 publications involving 109,506 participants were included. The meta-analysis showed that antidepressant use was not associated with colorectal cancer morbidity (relevant risk (RR): 0.97; 95% confidence interval (CI): 0.94-1.01) and mortality (RR: 1.08; 95% CI: 0.99-1.17). Subgroup analysis showed selective serotonin reuptake inhibitor (RR: 0.99; 95% CI: 0.96-1.03) or serotonin norepinephrine reuptake inhibitor (RR: 1.04; 95% CI: 0.86-1.26) were not associated with colorectal cancer risk; however, TCA was associated with colorectal cancer risk decrement (RR: 0.92; 95% CI: 0.87-0.98). Furthermore, the results also showed that antidepressant use was not associated with colorectal cancer risk in Europe and North America (RR: 0.97; 95% CI: 0.92-1.02) and Asia (RR: 1.00; 95% CI: 0.95-1.26). Additionally, a dose-response showed per 1 year of duration of antidepressant use incremental increase was not associated with colorectal cancer risk (RR: 0.96; 95% CI: 0.87-1.09).Evidence suggests that antidepressant use was not associated with colorectal cancer morbidity and mortality. The cumulative duration of antidepressant use did not utilized played critical roles.
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Affiliation(s)
| | - Xun Li
- Department of Clinical laboratory, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - Chengbin Li
- Department of Clinical laboratory, The Second Clinical Medical College, Yangtze University, Jingzhou, China
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16
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Wu Z, Wang G, Wang H, Xiao L, Wei Y, Yang C. Fluoxetine exposure for more than 2 days decreases the neuronal plasticity mediated by CRMP2 in differentiated PC12 cells. Brain Res Bull 2020; 158:99-107. [PMID: 32070769 DOI: 10.1016/j.brainresbull.2020.02.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 01/22/2020] [Accepted: 02/13/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Recent studies indicate that antidepressants treatment restores neuronal plasticity. In contrast, some researchers claim that serotonergic antidepressants, including fluoxetine (FLU), may exacerbate neuronal plasticity, which is contradictory and rarely studied. Since almost those studies exposed cells with drugs for 1-2 days as treatment models of antidepressants, it is possible that FLU exposure for longer periods would have opposite effects on neuronal plasticity. RESULTS In the present study, we examined the effects of FLU exposure (up to 3 days) on the neuronal plasticity in differentiated PC12 cells. The cell viability shown a slight decrease at day 2 (93.5 ± 3.5 %), followed by a highly significant decrease at day 3(71.4 ± 4.4 %). As previously reported, neuronal plasticity was significantly upregulated by FLU exposure at day 1. However, the neurite length, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos mRNA were inhibited with FLU exposure at day 3. Similarly, the expression of tubulin, which play important roles in the neuronal plasticity, was the same result. Furthermore, we found α-tubulin interacted with collapsing response mediator protein 2(CRMP2), which is related to neuronal plasticity, and the regulation of CRMP2 activity influenced the neurite length, Arc, c-Fos and tubulin expression. CONCLUSIONS The results demonstrated that neuronal plasticity was increased by FLU exposure at day 1, but exposure with FLU for more than 2 days had opposite effect on it. The reduction in neuronal plasticity with FLU exposure for more than 2 days might be involved in some aspects of the therapeutic effect of antidepressant on depression.
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Affiliation(s)
- Zuotian Wu
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road No.238, Wuhan, 430060, China.
| | - Gaohua Wang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road No.238, Wuhan, 430060, China.
| | - Huiling Wang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road No.238, Wuhan, 430060, China.
| | - Ling Xiao
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road No.238, Wuhan, 430060, China.
| | - Yanyan Wei
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road No.238, Wuhan, 430060, China.
| | - Can Yang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road No.238, Wuhan, 430060, China.
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17
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Barlaz Us S, Sogut F, Yildirim M, Yetkin D, Yalin S, Yilmaz SN, Comelekoglu U. Effect of Imipramine on radiosensitivity of Prostate Cancer: An In Vitro Study. Cancer Invest 2019; 37:489-500. [PMID: 31496302 DOI: 10.1080/07357907.2019.1662434] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Prostate cancer is the most common cancer and leading cause of cancer death for males. Imipramine (IMI), which is a tricyclic antidepressant, has also been shown to has antineoplastic effect. This study was performed to investigate the radiosensitizing effect of IMI on DU145 prostate cancer cell. Cells were divided into 4 groups. Cell index, apoptotic activity, cell cycle arrest, oxidative stress and EAG1 channel currents were determined in all groups. Our findings showed that combined treatment with IMI and radiotherapy (RAD) did not enhance radiosensitivity of DU145 cells but as unexpected finding, treatment of IMI alone was more effective in DU145 cells.
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Affiliation(s)
- Songul Barlaz Us
- Department of Radiation Oncology Mersin-Turkey, School of Medicine, Mersin University , Mersin , Turkey
| | - Fatma Sogut
- Department of Perfusion Technology, Vocational School of Medical Services, Mersin University , Mersin , Turkey
| | - Metin Yildirim
- Department of Biochemistry, School of Pharmacy, Mersin University , Mersin , Turkey
| | - Derya Yetkin
- Institute of Advanced Technology Research and Application, Mersin University , Mersin , Turkey
| | - Serap Yalin
- Department of Biochemistry, School of Pharmacy, Mersin University , Mersin , Turkey
| | - Sakir Necat Yilmaz
- Department of Histology-Embryology, School of Medicine, Mersin University , Mersin , Turkey
| | - Ulku Comelekoglu
- Department of Biophysics, School of Medicine, Mersin University , Mersin , Turkey
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18
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Rein T. Is Autophagy Involved in the Diverse Effects of Antidepressants? Cells 2019; 8:E44. [PMID: 30642024 PMCID: PMC6356221 DOI: 10.3390/cells8010044] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 01/08/2019] [Accepted: 01/09/2019] [Indexed: 02/06/2023] Open
Abstract
Autophagy has received increased attention as a conserved process governing cellular energy and protein homeostasis that is thus relevant in a range of physiological and pathophysiological conditions. Recently, autophagy has also been linked to depression, mainly through its involvement in the action of antidepressants. Some antidepressant drugs and psychotropic medication have been reported to exert beneficial effects in other diseases, for example, in cancer and neurodegenerative diseases. This review collates the evidence for the hypothesis that autophagy contributes to the effects of antidepressants beyond depression treatment.
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Affiliation(s)
- Theo Rein
- Max Planck Institute of Psychiatry, Munich 80804, Germany.
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19
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Kiridly-Calderbank JF, Sturgeon SR, Kroenke CH, Reeves KW. Antidepressant Use and Risk of Colorectal Cancer in the Women's Health Initiative. Cancer Epidemiol Biomarkers Prev 2018; 27:892-898. [PMID: 29789327 DOI: 10.1158/1055-9965.epi-17-1035] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 02/05/2018] [Accepted: 05/11/2018] [Indexed: 11/16/2022] Open
Abstract
Background: Some prior studies have reported reduced colorectal cancer risk among individuals using antidepressant medications, especially selective serotonin reuptake inhibitors (SSRIs). Yet most studies have not considered the potential role of depression or other confounders in their analyses.Methods: We utilized prospectively collected data from 145,190 participants in the Women's Health Initiative, among whom 2,580 incident colorectal cancer cases were diagnosed. Antidepressant use and depressive symptoms were assessed at baseline and follow-up study visits. Cox proportional hazards regression models with adjustment for depressive symptoms and other covariates were utilized to estimate HRs and 95% confidence intervals (CIs) for associations between antidepressant use and colorectal cancer.Results: Antidepressant use was reported by 6.9% of participants at baseline, with SSRIs the most common class of antidepressant used. In multivariable analyses, including adjustment for depressive symptomology, we observed no statistically significant association between antidepressant use overall (HR = 0.90; 95% CI, 0.75-1.09) or with SSRIs specifically (HR = 1.08; 95% CI, 0.85-1.37) and colorectal cancer risk. A borderline significant reduction in colorectal cancer risk was observed for use of tricyclic antidepressants (HR = 0.76; 95% CI, 0.56-1.04). Severe depressive symptoms were independently associated with a 20% increased risk of colorectal cancer (HR = 1.21; 95% CI, 1.09-1.48). Results were similar for separate evaluations of colon and rectal cancer.Conclusions: We observed no evidence of an association between antidepressant use, overall or by therapeutic class, and colorectal cancer risk.Impact: These results suggest that antidepressants may not be useful as chemopreventive agents for colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(8); 892-8. ©2018 AACR.
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Affiliation(s)
- Jenna F Kiridly-Calderbank
- Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, Massachusetts
| | - Susan R Sturgeon
- Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, Massachusetts
| | - Candyce H Kroenke
- Kaiser Permanente Northern California, Division of Research, Oakland, California
| | - Katherine W Reeves
- Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, Massachusetts.
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20
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Sawai H. Desipramine-induced lysosomal vacuolization is independent of autophagy. Cell Biol Int 2017; 42:248-253. [PMID: 29068103 DOI: 10.1002/cbin.10901] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/21/2017] [Indexed: 12/22/2022]
Abstract
Desipramine, a commonly used antidepressant drug, induced cytosolic vacuolization in L929 cells. The level of LC3-II was elevated and that of p62 was reduced in desipramine-treated L929 cells, indicating the induction of autophagy by desipramine. Surprisingly, massive vacuolization was observed in desipramine-treated L929 cells in the presence of LY294002, an inhibitor of autophagy. On the other hand, bafilomycin A1, an inhibitor of vacuolar type H+ ATPase, almost completely inhibited vacuolization in desipramine- or desipramine/LY294002-treated L929 cells. Furthermore, desipramine-induced vacuolization was observed in autophagy-deficient Atg7-/- mouse embryonic fibroblasts (MEFs) as well as wild-type Atg7+/+ MEFs. These results demonstrate that desipramine-induced lysosomal vacuolization is independent of autophagy.
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Affiliation(s)
- Hirofumi Sawai
- Department of Internal Medicine, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka, 573-1121, Japan
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21
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Cobanoglu H, Coskun M, Çayir A, Coskun M. In vitro genotoxic and cytotoxic effects of doxepin and escitalopram on human peripheral lymphocytes. Drug Chem Toxicol 2017; 41:238-244. [PMID: 28854817 DOI: 10.1080/01480545.2017.1365885] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Antidepressants are drugs used for the treatment of many psychiatric conditions including depression. There are findings suggesting that these drugs might have genotoxic, carcinogenic, and/or mutagenic effects. Therefore, the present in vitro study is intended to investigate potential genotoxic and cytotoxic effects of the antidepressants escitalopram (selective serotonin reuptake inhibitor) and doxepin (Tricyclic antidepressant) on human peripheral lymphocytes cytokinesis-block micronucleus (CBMN), sister chromatid exchange (SCE), and single cell gel electrophoresis (alkaline comet assay) were used for the purpose of the study. In the study, four different concentrations of both drugs (1, 2.5, 5, and 10 µg/mL) were administered to human peripheral lymphocytes for 24 h. The tested concentrations of both drugs were found to exhibit no cytotoxic and mitotic inhibitory effects. SCE increase caused by 5 and 10 µg/mL of escitalopram was found statistically significant, while no statistically significant increase was observed in DNA damage and micronucleus (MN) formation. Moreover, the increase caused by doxepin in MN formation was not found statistically significant. Besides, 10 µg/mL of doxepin was demonstrated to significantly increase arbitrary unit and SCE formation. These findings suggest that the investigated concentrations of escitalopram and doxepin were non-cytotoxic but potentially genotoxic at higher concentrations.
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Affiliation(s)
- Hayal Cobanoglu
- a Health Services Vocational College, Çanakkale Onsekiz Mart University , Çanakkale , Turkey
| | - Mahmut Coskun
- b Faculty of Medicine, Department of Medical Biology , Çanakkale Onsekiz Mart University , Terzioglu Campus , Çanakkale , Turkey
| | - Akin Çayir
- a Health Services Vocational College, Çanakkale Onsekiz Mart University , Çanakkale , Turkey
| | - Munevver Coskun
- a Health Services Vocational College, Çanakkale Onsekiz Mart University , Çanakkale , Turkey
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Serotonin transporter and receptor ligands with antidepressant activity as neuroprotective and proapoptotic agents. Pharmacol Rep 2017; 69:469-478. [DOI: 10.1016/j.pharep.2017.01.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 01/11/2017] [Accepted: 01/18/2017] [Indexed: 12/23/2022]
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Tran NQV, Nguyen AN, Takabe K, Yamagata Z, Miyake K. Pre-treatment with amitriptyline causes epigenetic up-regulation of neuroprotection-associated genes and has anti-apoptotic effects in mouse neuronal cells. Neurotoxicol Teratol 2017; 62:1-12. [PMID: 28511916 DOI: 10.1016/j.ntt.2017.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 05/09/2017] [Accepted: 05/11/2017] [Indexed: 12/12/2022]
Abstract
Antidepressants, such as imipramine and fluoxetine, are known to alter gene expression patterns by inducing changes in the epigenetic status of neuronal cells. There is also some evidence for the anti-apoptotic effect of various groups of antidepressants; however, this effect is complicated and cell-type dependent. Antidepressants of the tricyclic group, in particular amitriptyline, have been suggested to be beneficial in the treatment of neurodegenerative disorders. We examined whether amitriptyline exerts an anti-apoptotic effect via epigenetic mechanisms. Using DNA microarray, we analyzed global gene expression in mouse primary cultured neocortical neurons after treatment with amitriptyline and imipramine. The neuroprotection-associated genes, activating transcription factor 3 (Atf3) and heme oxygenase 1 (Hmox1), were up-regulated at both mRNA and protein levels by treatment with amitriptyline. Quantitative chromatin immunoprecipitation assay revealed that amitriptyline increased enrichments of trimethylation of histone H3 lysine 4 in the promoter regions of Atf3 and Hmox1 and acetylation of histone H3 lysine 9 in the promoter regions of Atf3, which indicate an active epigenetic status. Amitriptyline pre-treatment attenuated 1-methyl-4-phenylpyridinium ion (MPP+)- or amyloid β peptide 1-42 (Aβ1-42)-induced neuronal cell death and inhibited the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2). We found that Atf3 and Hmox1 were also up-regulated after Aβ1-42 treatment, and were further increased when pre-treated with amitriptyline. Interestingly, the highest up-regulation of Atf3 and Hmox1, at least at mRNA level, was observed after co-treatment with Aβ1-42 and amitriptyline, together with the loss of the neuroprotective effect. These findings suggest preconditioning and neuroprotective effects of amitriptyline; however, further investigations are needed for clarifying the contribution of epigenetic up-regulation of Atf3 and Hmox1 genes.
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Affiliation(s)
- Nguyen Quoc Vuong Tran
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan
| | - An Nghia Nguyen
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan
| | - Kyoko Takabe
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan
| | - Zentaro Yamagata
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan
| | - Kunio Miyake
- Department of Health Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan.
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Charles E, Hammadi M, Kischel P, Delcroix V, Demaurex N, Castelbou C, Vacher AM, Devin A, Ducret T, Nunes P, Vacher P. The antidepressant fluoxetine induces necrosis by energy depletion and mitochondrial calcium overload. Oncotarget 2017; 8:3181-3196. [PMID: 27911858 PMCID: PMC5356874 DOI: 10.18632/oncotarget.13689] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 11/21/2016] [Indexed: 11/25/2022] Open
Abstract
Selective Serotonin Reuptake Inhibitor antidepressants, such as fluoxetine (Prozac), have been shown to induce cell death in cancer cells, paving the way for their potential use as cancer therapy. These compounds are able to increase cytosolic calcium concentration ([Ca2+]cyt), but the involved mechanisms and their physiological consequences are still not well understood. Here, we show that fluoxetine induces an increase in [Ca2+]cyt by emptying the endoplasmic reticulum (ER) through the translocon, an ER Ca2+ leakage structure. Our data also show that fluoxetine inhibits oxygen consumption and lowers mitochondrial ATP. This latter is essential for Ca2+ reuptake into the ER, and we postulated therefore that the fluoxetine-induced decrease in mitochondrial ATP production results in the emptying of the ER, leading to capacitative calcium entry. Furthermore, Ca2+ quickly accumulated in the mitochondria, leading to mitochondrial Ca2+ overload and cell death. We found that fluoxetine could induce an early necrosis in human peripheral blood lymphocytes and Jurkat cells, and could also induce late apoptosis, especially in the tumor cell line. These results shed light on fluoxetine-induced cell death and its potential use in cancer treatment.
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Affiliation(s)
- Emilie Charles
- INSERM U1218, Institut Bergonié, Bordeaux, France
- Université de Bordeaux, Bordeaux, France
| | - Mehdi Hammadi
- INSERM U1218, Institut Bergonié, Bordeaux, France
- Université de Bordeaux, Bordeaux, France
| | - Philippe Kischel
- Laboratory of Cellular and Molecular Physiology EA4667, Université de Picardie Jules Verne, SFR CAP-SANTE (FED 4231), Amiens, France
| | - Vanessa Delcroix
- INSERM U1218, Institut Bergonié, Bordeaux, France
- Université de Bordeaux, Bordeaux, France
| | - Nicolas Demaurex
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Cyril Castelbou
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Anne-Marie Vacher
- INSERM U1218, Institut Bergonié, Bordeaux, France
- Université de Bordeaux, Bordeaux, France
| | - Anne Devin
- Institut de Biochimie et Génétique Cellulaires, UMR 5095, Bordeaux, France
- Université de Bordeaux, Bordeaux, France
| | - Thomas Ducret
- INSERM U1045, Centre de Recherche Cardio-Thoracique, Bordeaux, France
- Université de Bordeaux, Bordeaux, France
| | - Paula Nunes
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Pierre Vacher
- INSERM U1218, Institut Bergonié, Bordeaux, France
- Université de Bordeaux, Bordeaux, France
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Bowie M, Pilie P, Wulfkuhle J, Lem S, Hoffman A, Desai S, Petricoin E, Carter A, Ambrose A, Seewaldt V, Yu D, Ibarra Drendall C. Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer. World J Clin Oncol 2015; 6:299-311. [PMID: 26677444 PMCID: PMC4675916 DOI: 10.5306/wjco.v6.i6.299] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 09/08/2015] [Accepted: 10/27/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mechanism of action of lipophilic antidepressant fluoxetine (FLX) in representative molecular subtypes of breast cancer.
METHODS: The anti-proliferative effects and mechanistic action of FLX in triple-negative (SUM149PT) and luminal (T47D and Au565) cancer cells and non-transformed MCF10A were investigated. Reverse phase protein microarray (RPPM) was performed with and without 10 μmol/L FLX for 24 and 48 h to determine which proteins are significantly changed. Viability and cell cycle analysis were also performed to determine drug effects on cell growth. Western blotting was used to confirm the change in protein expression examined by RPPM or pursue other signaling proteins.
RESULTS: The FLX-induced cell growth inhibition in all cell lines was concentration- and time-dependent but less pronounced in early passage MCF10A. In comparison to the other lines, cell growth reduction in SUM149PT coincided with significant induction of endoplasmic reticulum (ER) stress and autophagy after 24 and 48 h of 10 μmol/L FLX, resulting in decreased translation of proteins along the receptor tyrosine kinase/Akt/mammalian target of rapamycin pathways. The increase in autophagy marker, cleaved microtubule-associated protein 1 light chain 3, in SUM149PT after 24 h of FLX was likely due to increased metabolic demands of rapidly dividing cells and ER stress. Consequently, the unfolded protein response mediated by double-stranded RNA-dependent protein kinase-like ER kinase resulted in inhibition of protein synthesis, growth arrest at the G1 phase, autophagy, and caspase-7-mediated cell death.
CONCLUSION: Our study suggests a new role for FLX as an inducer of ER stress and autophagy, resulting in death of aggressive triple negative breast cancer SUM149PT.
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Anti-depressant therapy and cancer risk: a nested case-control study. Eur Neuropsychopharmacol 2015; 25:1147-57. [PMID: 25934397 DOI: 10.1016/j.euroneuro.2015.04.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 03/28/2015] [Accepted: 04/03/2015] [Indexed: 11/21/2022]
Abstract
UNLABELLED Previous studies demonstrated a possible association between anti-depressant therapy with selective serotonin reuptake inhibitors (SSRI) and tricyclic anti-depressants (TCA), several genetic and hormonal pathways and cancer risk, with inconsistent results. Exposure to serotonin-norepinephrine reuptake inhibitors (SNRI) was not studied extensively. We sought to evaluate the association between exposure to SSRIs, TCAs and SNRIs and the five most common solid tumors. We conducted nested case-control studies using a large UK population-representative database. Cases were those with any medical code for the specific malignancy. For every case, four controls matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence-density sampling. Exposure of interest was SSRI, SNRI or TCA therapy before index date. Odds ratios (ORs) and 95% CIs were estimated for each anti-depressant class using conditional logistic-regression analysis, adjusted for potential confounders, such as obesity, smoking history and alcohol consumption. RESULTS 109,096 cancer patients and 426,402 matched controls were included. Current SSRI users with treatment initiation>one year before index date had modestly higher risk for lung and breast cancers with ORs of 1.27 (95% CI 1.16-1.38) and 1.12 (95% CI 1.06-1.18), respectively. Among current TCA users, there was a higher risk only for lung cancers with OR of 1.45 (95% CI 1.31-1.6). There was no statistically significant association between current SNRI therapy and cancer risk. DISCUSSION Treatment with SSRI and TCA might be associated with increased lung cancer risk. SSRI therapy might be associated with modest increase in breast cancer risk.
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27
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Norizadeh Tazehkand M, Topaktas M. Thein vitrogenotoxic and cytotoxic effects of remeron on human peripheral blood lymphocytes. Drug Chem Toxicol 2014; 38:266-71. [DOI: 10.3109/01480545.2014.947425] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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28
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Zerbini LF, Bhasin MK, de Vasconcellos JF, Paccez JD, Gu X, Kung AL, Libermann TA. Computational repositioning and preclinical validation of pentamidine for renal cell cancer. Mol Cancer Ther 2014; 13:1929-1941. [PMID: 24785412 DOI: 10.1158/1535-7163.mct-13-0750] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although early stages of clear cell renal cell carcinoma (ccRCC) are curable, survival outcome for metastatic ccRCC remains poor. We previously established a highly accurate signature of differentially expressed genes that distinguish ccRCC from normal kidney. The purpose of this study was to apply a new individualized bioinformatics analysis (IBA) strategy to these transcriptome data in conjunction with Gene Set Enrichment Analysis of the Connectivity Map (C-MAP) database to identify and reposition FDA-approved drugs for anticancer therapy. Here, we demonstrate that one of the drugs predicted to revert the RCC gene signature toward normal kidney, pentamidine, is effective against RCC cells in culture and in a RCC xenograft model. ccRCC-specific gene expression signatures of individual patients were used to query the C-MAP software. Eight drugs with negative correlation and P-value <0.05 were analyzed for efficacy against RCC in vitro and in vivo. Our data demonstrate consistency across most patients with ccRCC for the set of high-scoring drugs. Most of the selected high-scoring drugs potently induce apoptosis in RCC cells. Several drugs also demonstrate selectivity for Von Hippel-Lindau negative RCC cells. Most importantly, at least one of these drugs, pentamidine, slows tumor growth in the 786-O human ccRCC xenograft mouse model. Our findings suggest that pentamidine might be a new therapeutic agent to be combined with current standard-of-care regimens for patients with metastatic ccRCC and support our notion that IBA combined with C-MAP analysis enables repurposing of FDA-approved drugs for potential anti-RCC therapy.
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Affiliation(s)
- Luiz Fernando Zerbini
- International Center for Genetic Engineering and Biotechnology (ICGEB), Cancer Genomics Group and Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.,BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
| | - Manoj K Bhasin
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
| | - Jaira F de Vasconcellos
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
| | - Juliano D Paccez
- International Center for Genetic Engineering and Biotechnology (ICGEB), Cancer Genomics Group and Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa
| | - Xuesong Gu
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
| | - Andrew L Kung
- Department of Pediatrics, Columbia University Medical Center, New York, NY
| | - Towia A Libermann
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Grygier B, Arteta B, Kubera M, Basta-Kaim A, Budziszewska B, Leśkiewicz M, Curzytek K, Duda W, Lasoń W, Maes M. Inhibitory effect of antidepressants on B16F10 melanoma tumor growth. Pharmacol Rep 2014; 65:672-81. [PMID: 23950590 DOI: 10.1016/s1734-1140(13)71045-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 12/11/2012] [Indexed: 12/27/2022]
Abstract
BACKGROUND Antidepressant drugs, like fluoxetine, a selective serotonin reuptake inhibitor, desipramine, a nonselective noradrenaline reuptake inhibitor, and mirtazapine, an antagonist of noradrenaline α2 auto- and heteroreceptors, are widely used for the treatment of depressive symptoms in cancer patients. Since these antidepressants have different activities targeting the immune system, they might also modulate tumor growth in cancer patients. METHODS In the present study, we investigated the effects of administration of antidepressant drugs: fluoxetine, desipramine and mirtazapine on B16F10 melanoma tumor growth. These drugs were administered intraperitoneally (ip) for 17 days after subcutaneous injection of B16F10 melanoma cells to male C57BL/6J mice. RESULTS Fluoxetine significantly inhibited melanoma solid tumor growth and desipramine tended to decrease this parameter whereas mirtazapine had no effect. CONCLUSION The inhibitory effect of fluoxetine on melanoma growth was associated with an increased mitogen-induced T cell proliferation which may at least partly participate in the mechanism of the antitumor effect of this antidepressant. It appears that the inhibitory effect of fluoxetine on tumor growth is not related with changes in cytokine levels except for IL-10.
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Affiliation(s)
- Beata Grygier
- Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
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Sun LM, Lin MC, Liang JA, Chang YJ, Chang SN, Sung FC, Muo CH, Kao CH. Does use of tetracyclic antidepressant-mirtazapine reduce cancer risk in depression patients? Pharmacoepidemiol Drug Saf 2013; 22:1292-7. [PMID: 24115340 DOI: 10.1002/pds.3523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 07/09/2013] [Accepted: 08/25/2013] [Indexed: 11/12/2022]
Abstract
PURPOSE We conducted a nested case-control study to evaluate the association between risk of cancer and mirtazapine use in depression patients in Taiwan. METHODS We obtained data from the Taiwan National Health Insurance Research Database to conduct a population-based nested case-control study. The study cohort included 16 897 patients diagnosed with depression between January 1, 2000 and December 31, 2008. We identified 530 cancer patients as the study group and matched 4 non-cancer subjects with each cancer patient by incident density, age, and sex. Odds ratios and 95% confidence intervals were estimated using multivariate conditional logistic regression analysis. RESULTS Use of mirtazapine for depression did not have significant effect on overall cancer incidence (odds ratio: 1.03, 95% confidence interval: 0.72-1.48). Further analysis of annual mirtazapine dosages and the duration of mirtazapine use revealed no significant effect on cancer risk. CONCLUSION The findings of this population-based nested case-control study suggest that mirtazapine use may not provide a tumor suppression effect in humans such as that seen in the animal model. Future large-scale and in-depth investigations in this area are warranted.
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Affiliation(s)
- Li-Min Sun
- Department of Radiation Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
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The tricyclic antidepressant amitriptyline is cytotoxic to HTB114 human leiomyosarcoma and induces p75NTR-dependent apoptosis. Anticancer Drugs 2013; 24:899-910. [DOI: 10.1097/cad.0b013e328364312f] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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32
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Hodge JM, Wang Y, Berk M, Collier FM, Fernandes TJ, Constable MJ, Pasco JA, Dodd S, Nicholson GC, Kennedy RL, Williams LJ. Selective serotonin reuptake inhibitors inhibit human osteoclast and osteoblast formation and function. Biol Psychiatry 2013; 74:32-9. [PMID: 23260229 DOI: 10.1016/j.biopsych.2012.11.003] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Revised: 10/08/2012] [Accepted: 11/06/2012] [Indexed: 01/28/2023]
Abstract
BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants and one of the most commonly used medications. There is growing concern that SSRIs, which sequester in bone marrow at higher concentrations than brain or blood, increase bone fragility and fracture risk. However, their mechanism of action on human osteoclasts (OC) and osteoblasts (OB) differentiation remains unclear. METHODS Expression of serotonin receptors (5-HTR), transporter (5-HTT), and tryptophan hydroxylase 1 (TPH1) was assessed in human OC (precursors and mature) and OB (nonmineralizing and mineralizing) by polymerase chain reaction. OC formation and resorption was measured in the presence of 5 SSRIs. OBs cultured with SSRIs for 28 days were assessed for alkaline phosphatase (ALP) and bone mineralization. Cell viability and apoptosis were determined by annexin V flow cytometry. RESULTS OCs and OB expressed TPH1, 5-HTT, and 5-HTR1B. The 5-HTR2A was expressed only in OB, whereas 5-HTR2B expression increased from precursor to mature OC. All SSRIs (except citalopram) dose-dependently inhibited OC formation and resorption between 1 μmol/L and 10 μmol/L; order of potency: sertraline > fluoxetine > paroxetine > fluvoxamine > citalopram. Similarly, SSRIs (except citalopram) inhibited ALP and bone mineralization by OB but only at 30 μmol/L. Apoptosis was induced by SSRIs in OC and OB in an identical pattern to inhibitory effects. Serotonin treatment had no effect on either OC or OB parameters. CONCLUSIONS These data demonstrate that SSRIs differentially inhibit bone cell function via apoptosis. This may explain the mechanisms of bone loss with chronic use and aid clinical choices.
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Affiliation(s)
- Jason M Hodge
- Barwon Biomedical Research, The Geelong Hospital, Geelong, Victoria, Australia
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Antidepressants: influence on cancer and immunity? Life Sci 2013; 92:525-32. [PMID: 23369745 DOI: 10.1016/j.lfs.2013.01.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Revised: 12/10/2012] [Accepted: 01/16/2013] [Indexed: 01/10/2023]
Abstract
Two decades ago, it was hypothesized that antidepressants could alter the course of neoplastic diseases. However, contradictory findings indicated that antidepressants could either have carcinogenic properties or improve the disease outcome. Intriguingly, controversial results were reported on the action of antidepressant drugs on immune function. Further hypotheses proposed that antidepressants could indirectly affect the cancer prognosis through the modulation of antitumor activity. Here we review the literature in order to elucidate the influence of antidepressants on cancer and immunity.
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Walker AJ, Grainge M, Bates TE, Card TR. Survival of glioma and colorectal cancer patients using tricyclic antidepressants post-diagnosis. Cancer Causes Control 2012; 23:1959-64. [PMID: 23065071 DOI: 10.1007/s10552-012-0073-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 10/01/2012] [Indexed: 01/30/2023]
Abstract
BACKGROUND Tricyclic antidepressants have been demonstrated in the laboratory to have anticancer properties. A recent study by our group also suggested a protective effect against development of colorectal cancer and glioma. This study aims to determine whether the anticancer action of tricyclics translates to improved survival in these cancers post-diagnosis. METHODS A study using the General Practice Research Database examined whether tricyclic antidepressant exposure in the months following diagnosis of glioma or colorectal cancer would affect longer term all-cause mortality. Cox proportional hazards modelling adjusted for age, gender, smoking, body mass index, comorbidity, and diagnosed depression. RESULTS A cohort of 1,364 glioma and 16,519 colorectal cancer patients were identified. There was a non-significant reduction in the hazard for glioma patients treated with tricyclics (HR = 0.83, CI = 0.53-1.30). This was mainly found in patients who were not previously exposed to tricyclics (HR = 0.56, CI = 0.26-1.18). In contrast, a significant increase in hazard was found for colorectal cancer (HR = 1.37, CI = 1.21-1.54). This was mostly in patients prescribed low-dose tricyclics (HR = 1.57, CI = 1.33-1.86). CONCLUSIONS We have shown no significant mortality reduction in colorectal cancer or glioma patients treated with tricyclics. An apparent detrimental effect observed in colorectal cancer may be related to prescription of low-dose tricyclics in the management of pain related to disseminated cancer. We cannot rule out small effects or an effect that occurs exclusively at higher doses. Blinded clinical studies may therefore be the only method of determining efficacy in glioma patients.
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Affiliation(s)
- Alex J Walker
- Division of Epidemiology and Public Health, School of Community Health Sciences, Nottingham City Hospital, University of Nottingham, Clinical Sciences Building, Nottingham, NG5 1PB, UK.
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Fang CK, Chen HW, Chiang IT, Chen CC, Liao JF, Su TP, Tung CY, Uchitomi Y, Hwang JJ. Mirtazapine inhibits tumor growth via immune response and serotonergic system. PLoS One 2012; 7:e38886. [PMID: 22808019 PMCID: PMC3396612 DOI: 10.1371/journal.pone.0038886] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Accepted: 05/14/2012] [Indexed: 02/06/2023] Open
Abstract
To study the tumor inhibition effect of mirtazapine, a drug for patients with depression, CT26/luc colon carcinoma-bearing animal model was used. BALB/c mice were randomly divided into six groups: two groups without tumors, i.e. wild-type (no drug) and drug (mirtazapine), and four groups with tumors, i.e. never (no drug), always (pre-drug, i.e. drug treatment before tumor inoculation and throughout the experiment), concurrent (simultaneously tumor inoculation and drug treatment throughout the experiment), and after (post-drug, i.e. drug treatment after tumor inoculation and throughout the experiment). The “psychiatric” conditions of mice were observed from the immobility time with tail suspension and spontaneous motor activity post tumor inoculation. Significant increase of serum interlukin-12 (sIL-12) and the inhibition of tumor growth were found in mirtazapine-treated mice (always, concurrent, and after) as compared with that of never. In addition, interferon-γ level and immunocompetent infiltrating CD4+/CD8+ T cells in the tumors of mirtazapine-treated, tumor-bearing mice were significantly higher as compared with that of never. Tumor necrosis factor-α (TNF-α) expressions, on the contrary, are decreased in the mirtazapine-treated, tumor-bearing mice as compared with that of never. Ex vivo autoradiography with [123I]ADAM, a radiopharmaceutical for serotonin transporter, also confirms the similar results. Notably, better survival rates and intervals were also found in mirtazapine-treated mice. These findings, however, were not observed in the immunodeficient mice. Our results suggest that tumor growth inhibition by mirtazapine in CT26/luc colon carcinoma-bearing mice may be due to the alteration of the tumor microenvironment, which involves the activation of the immune response and the recovery of serotonin level.
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Affiliation(s)
- Chun-Kai Fang
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
- Department of Psychiatry and Suicide Prevention Center, Mackay Memorial Hospital, Taipei, Taiwan
| | - Hong-Wen Chen
- Department of Radiation Oncology and Hospice Palliative Care Center, Mackay Memorial Hospital, Taipei, Taiwan
| | - I-Tsang Chiang
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
| | | | - Jyh-Fei Liao
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Ton-Ping Su
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chieh-Yin Tung
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Yosuke Uchitomi
- Department of Neuropsychiatry, School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama-shi, Japan
| | - Jeng-Jong Hwang
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
- * E-mail:
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The effect of tricyclic antidepressants on cutaneous melanoma cell lines and primary cell cultures. Anticancer Drugs 2012; 23:65-9. [PMID: 21897201 DOI: 10.1097/cad.0b013e32834b1894] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The tricyclic antidepressants have previously been shown to exert activity against glioma cells in vitro. Initial studies in cell lines suggested that this might extend to melanoma cells. We have therefore conducted a study in primary cell cultures from metastatic cutaneous melanoma deposits using a well established ATP-based tumour chemosensitivity assay to confirm and extend these findings. Two cell lines and eight primary cell cultures from metastatic melanoma deposits were exposed to three tricyclic drugs, amitriptyline, nortriptyline and clomipramine, at concentrations ranging from 200 to 6.25 µmol/l in the ATP-based tumour chemosensitivity assay. All three drugs showed activity, although nortriptyline was more active than clomipramine or amitriptyline in both cell lines and primary cell cultures, with an IC50 of 9, 27 and 33 µmol/l, respectively. Tricyclic agents show activity against melanoma in vitro. This could be related to the lysosomal effects based on their cationic amphiphilic properties, or effects at the mitochondrial membrane.
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Kabolizadeh P, Engelmann BJ, Pullen N, Stewart JK, Ryan JJ, Farrell NP. Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells. J Biol Inorg Chem 2012; 17:123-32. [PMID: 21918844 PMCID: PMC3250067 DOI: 10.1007/s00775-011-0836-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Accepted: 08/08/2011] [Indexed: 01/11/2023]
Abstract
A unique synergistic effect on platinum drug cytotoxicity is noted in the presence of the tricyclic antidepressant desipramine. Desipramine is used for treating neuropathic pain, particularly in prostate cancer patients. The clinically used drugs cisplatin (cis-[PtCl(2)(NH(3))(2)]), oxaliplatin [1,2-diaminocyclohexaneoxalatoplatinum(II)], and the cationic trinuclear agent BBR3464 [{trans-PtCl(NH(3))(2)}(2)-μ-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2))](4+), which has undergone evaluation in phase II clinical trials for activity in lung and ovarian cancers, were evaluated. Surprisingly, desipramine greatly augments the cytotoxicity of all the platinum-based chemotherapeutics in HCT116 colorectal carcinoma cell lines. Desipramine enhanced cellular accumulation of cisplatin, but had no effect on the accumulation of oxaliplatin or BBR3464, suggesting that enhanced accumulation could not be a consistent means by which desipramine altered the platinum-drug-mediated cytotoxicity. The desipramine/cisplatin combination resulted in increased levels of p53 as well as mitochondrial damage, caspase activation, and poly(ADP ribose) polymerase cleavage, suggesting that desipramine may synergize with cisplatin more than with other platinum chemotherapeutics partly by activating distinct apoptotic pathways. The study argues that desipramine may be a means of enhancing chemoresponsiveness of platinum drugs and the results warrant further investigation. The results emphasize the importance of understanding the differential pharmacological action of adjuvants employed in combinations with cancer chemotherapeutics.
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Affiliation(s)
- Peyman Kabolizadeh
- Department of Chemistry, Virginia Commonwealth University, 1001 W. Main St., Richmond, VA 23284, USA
| | - Brigitte J. Engelmann
- Department of Chemistry, Virginia Commonwealth University, 1001 W. Main St., Richmond, VA 23284, USA
| | - Nicholas Pullen
- Department of Biology, Virginia Commonwealth University, Richmond, VA, USA
| | | | - John J. Ryan
- Department of Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Nicholas P. Farrell
- Department of Chemistry, Virginia Commonwealth University, 1001 W. Main St., Richmond, VA 23284, USA
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Cavalla D, Singal C. Retrospective clinical analysis for drug rescue: for new indications or stratified patient groups. Drug Discov Today 2011; 17:104-9. [PMID: 22001144 DOI: 10.1016/j.drudis.2011.09.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Revised: 09/20/2011] [Accepted: 09/30/2011] [Indexed: 12/19/2022]
Abstract
The increasing realization that many existing drugs do indeed provide opportunities for additional therapeutic indications suggests we should not only be alert for this potential among marketed drugs but also within the pool of developmental drugs, of which (owing to attrition) there are many more examples in existence. We present examples of drug repurposing by retrospective clinical trial analysis and suggest that this strategy presents a promising way of rescuing failed developmental candidates. We contend that the commercial barriers to successful drug rescue are less problematic than for drug repurposing. We indicate practical means for mining data from past clinical trials, either for new indications or for specific patient groups.
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Vircheva S, Nenkova G, Georgieva A, Alexandrova A, Tzvetanova E, Mateeva P, Zamfirova R, Kirkova M. Effects of desipramine on the antioxidant status in rat tissues at carrageenan-induced paw inflammation. Cell Biochem Funct 2011; 30:18-23. [PMID: 21953526 DOI: 10.1002/cbf.1812] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 08/15/2011] [Accepted: 08/24/2011] [Indexed: 12/28/2022]
Abstract
The pathogenesis of many diseases and different pathological conditions, including inflammation, is associated with excess production of reactive oxygen species (ROS). The present study aimed to investigate the effects of the antidepressant desipramine (DES) on carrageenan (CG)-induced inflammation, as well as on the endogenous levels of cell enzyme and non-enzyme antioxidants in rat liver and spleen, 4 and 24 h after CG injection. The intra-plantar CG injection into the right hind paw resulted in a time-dependent increase in the paw volume; the maximum of CG-induced edema peak was in 2-4 h. A single DES dose of 20 mg · kg(-1) , administered 30 min before CG, had no effect on paw edema, whereas the higher drug dose used (50 mg · kg(-1) ) suppressed the edematous response to CG. The latter drug dose protected CG-induced decrease of glutathione (non-enzyme antioxidant) in the liver; it did not affect CG-unchanged activities of superoxide dismutase, glutathione peroxidase (enzyme antioxidants) and glucose-6-phosphate dehydrogenase (enzyme, important for the activity of glutathione-conjugated antioxidant enzymes) in both liver and spleen. The drug showed an efficient antioxidant capacity in ROS-generating chemical systems; it was higher than that of fluoxetine (another type of antidepressant). The present results suggest that the good antioxidant activity of DES might contribute to its beneficial effects in liver injuries.
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Affiliation(s)
- Stefani Vircheva
- Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
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Jeon SH, Kim SH, Kim Y, Kim YS, Lim Y, Lee YH, Shin SY. The tricyclic antidepressant imipramine induces autophagic cell death in U-87MG glioma cells. Biochem Biophys Res Commun 2011; 413:311-7. [DOI: 10.1016/j.bbrc.2011.08.093] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Accepted: 08/19/2011] [Indexed: 12/11/2022]
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Dikmen M, Cantürk Z, Oztürk Y. Escitalopram oxalate, a selective serotonin reuptake inhibitor, exhibits cytotoxic and apoptotic effects in glioma C6 cells. Acta Neuropsychiatr 2011; 23:173-8. [PMID: 25379795 DOI: 10.1111/j.1601-5215.2011.00550.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Dikmen M, Cantürk Z, Öztürk Y. Escitalopram oxalate, a selective serotonin reuptake inhibitor, exhibits cytotoxic and apoptotic effects in glioma C6 cells.Objective: Various antidepressants, mainly tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have been reported to exhibit potent anticancer properties in different cancer cells. In this study, we evaluated the antiproliferative and apoptotic effects of escitalopram oxalate (25, 50, 100 and 200 µM) on rat C6 glioma cells.Methods: Cell proliferations were measured by [3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide] (MTT) assay, apoptosis was observed by flow cytometric analysis on C6 cells.Results: Significant decreases in the proliferation of C6 glioma cells were detected depending on increases in the escitalopram concentrations and incubation periods. When compared to controls, C6 cell proliferations after 24 h incubation were determined with 97.7, 85.9, 74.5 and 67.9% for 25, 50, 100 and 200 µM escitalopram, respectively, while the cell proliferations after 48 h were established as 96.5, 68.0, 50.7 and 39.9% for 25, 50, 100 and 200 µM concentrations, respectively. IC50 value of escitalopram was able to be calculated as 106.97 µM after 48 h. Based on Annexin V-propidium iodide (PI) binding capacity for 25, 50, 100 and 200 µM escitalopram, apoptotic effects were determined as 17.0, 22.3, 12.5 and 7.8%, respectively.Conclusion: Based on our findings, escitalopram oxalate was observed to induce cytotoxic and apoptotic activities in C6 cells.
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Affiliation(s)
- Miriş Dikmen
- Faculty of Pharmacy, Department of Pharmacology, Anadolu University, Eskisehir, Turkey
| | - Zerrin Cantürk
- Faculty of Pharmacy, Department of Pharmaceutical Microbiology, Anadolu University, Eskisehir, Turkey
| | - Yusuf Oztürk
- Faculty of Pharmacy, Department of Pharmacology, Anadolu University, Eskisehir, Turkey
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Fluoxetine induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats. Toxicol Lett 2011; 204:134-40. [PMID: 21554931 DOI: 10.1016/j.toxlet.2011.04.024] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 04/20/2011] [Accepted: 04/21/2011] [Indexed: 12/17/2022]
Abstract
Fluoxetine (FLX) is a drug commonly used as antidepressant. However, its effects on tumorigenesis remain controversial. Aiming to evaluate the effects of FLX treatment on early malignant changes, we analyzed serotonin (5-HT) metabolism and recognition, aberrant crypt foci (ACF), proliferative process, microvessels, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) expression in colon tissue. Male Wistar rats received a daily FLX-gavage (30mgkg(-1)) and, a single dose of 1,2 dimethylhydrazine (DMH; i.p., 125mgkg(-1)). After 6 weeks of FLX-treatment, our results revealed that FLX and nor-fluoxetine (N-FLX) are present in colon tissue, which was related to significant increase in serotonin (5-HT) levels (P<0.05) possibly through a blockade in SERT mRNA (serotonin reuptake transporter; P<0.05) resulting in lower 5-hydroxyindoleacetic acid (5-HIAA) levels (P<0.01) and, 5-HT2C receptor mRNA expressions. FLX-treatment decreased dysplastic ACF development (P<0.01) and proliferative process (P<0.001) in epithelia. We observed a significant decrease in the development of malignant microvessels (P<0.05), VEGF (P<0.001), and COX-2 expression (P<0.01). These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue, probably due to its modulatory activity on 5-HT metabolism and/or its ability to reduce colonic malignant events.
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Frick LR, Rapanelli M, Arcos MLB, Cremaschi GA, Genaro AM. Oral administration of fluoxetine alters the proliferation/apoptosis balance of lymphoma cells and up-regulates T cell immunity in tumor-bearing mice. Eur J Pharmacol 2011; 659:265-72. [PMID: 21497159 DOI: 10.1016/j.ejphar.2011.03.037] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Revised: 03/02/2011] [Accepted: 03/22/2011] [Indexed: 11/19/2022]
Abstract
Antidepressants have a controversial role with regard to their influence on cancer and immunity. Recently, we showed that fluoxetine administration induces an enhancement of the T-cell mediated immunity in naïve mice, resulting in the inhibition of tumor growth. Here we studied the effects of fluoxetine on lymphoma proliferation/apoptosis and immunity in tumor bearing-mice. We found an increase of apoptotic cells (active Caspase-3(+)) and a decrease of proliferative cells (PCNA(+)) in tumors growing in fluoxetine-treated animals. In addition, differential gene expressions of cell cycle and death markers were observed. Cyclins D3, E and B were reduced in tumors from animals treated with fluoxetine, whereas the tumor suppressor p53 and the cell cycle inhibitors p15/INK4B, p16/INK4A and p27/Kip1 were increased. Besides, the expression of the antiapoptotic factor Bcl-2 and the proapoptotic factor Bad were lower and higher respectively in these animals. These changes were accompanied by increased IFN-γ and TNF-α levels as well as augmented circulating CD8(+) T lymphocytes in tumor-bearing mice treated with the antidepressant. Therefore, we propose that the up-regulation of T-cell mediated antitumor immunity may be contributing to the alterations of tumor cell proliferation and apoptosis thus resulting in the inhibition of tumor progression.
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Affiliation(s)
- Luciana Romina Frick
- Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Científicas y Técnicas, 1° Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155 Piso 15, Buenos Aires (1121), Argentina.
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Mao X, Hou T, Cao B, Wang W, Li Z, Chen S, Fei M, Hurren R, Gronda M, Wu D, Trudel S, Schimmer AD. The tricyclic antidepressant amitriptyline inhibits D-cyclin transactivation and induces myeloma cell apoptosis by inhibiting histone deacetylases: in vitro and in silico evidence. Mol Pharmacol 2011; 79:672-80. [PMID: 21220410 DOI: 10.1124/mol.110.068122] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Amitriptyline is a classic tricyclic antidepressant (TCA) and has been used to treat the depression and anxiety of patients with cancer, but its relevance to cancer cell apoptosis is not known. In the present study, we demonstrated that amitriptyline inhibited cyclin D2 transactivation and displayed potential antimyeloma activity by inhibiting histone deacetylases (HDACs). Amitriptyline markedly decreased cyclin D2 promoter-driven luciferase activity, reduced cyclin D2 expression, and arrested cells at the G(0)/G(1) phase of the cell cycle. Amitriptyline-induced apoptosis was confirmed by Annexin V staining, and cleavage of caspase-3 and poly(ADP-ribose) polymerase-1. D-Cyclin expression is reported to be epigenetically regulated by histone acetylation. Thus, we examined the effects of amitriptyline on histone 3 (H3) acetylation and demonstrated that amitriptyline increased acetylation of H3 and expression of p27 and p21. Further studies indicated that amitriptyline interfered with HDAC function by down-regulation of HDAC3, -6, -7, and -8, but not HDAC2, and by interacting with HDAC7. Molecular docking analysis and molecular dynamics simulations revealed that amitriptyline bound to HDAC7 and formed strong van der Waals interactions with five residues of HDAC7, including Phe162, His192, Phe221, Leu293, and His326, thus inhibiting HDAC activity. Therefore, we found that amitriptyline inhibited cyclin D2 transactivation and HDAC activity and could be a promising treatment for multiple myeloma.
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Affiliation(s)
- Xinliang Mao
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China.
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Chubak J, Boudreau DM, Rulyak SJ, Mandelson MT. Colorectal cancer risk in relation to antidepressant medication use. Int J Cancer 2011; 128:227-32. [PMID: 20232382 PMCID: PMC2962879 DOI: 10.1002/ijc.25322] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Laboratory studies suggest that antidepressants affect the risk of some cancers, including colorectal cancer. To investigate whether selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are associated with colorectal cancer risk, we conducted a case-control study among enrollees of an integrated healthcare delivery system in Washington State. Cases were first diagnosed with invasive colorectal cancer between 2000 and 2003; controls were randomly selected from Group Health enrollees and matched to cases on age, sex and length of enrollment before diagnosis/reference date. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for colorectal cancer in relation to use of any antidepressant, SSRIs only or TCAs only, among 649 cases and 656 controls. Use of any antidepressant was associated with a reduced risk of colorectal cancer (OR = 0.7, 95% CI = 0.5-0.9). Associations were similar for persons who used SSRIs exclusively (OR = 0.7, 95% CI = 0.4-1.1) and TCAs exclusively (OR = 0.7, 95% CI = 0.5-1.2); however, this reduction in risk appeared limited to persons without a prior cancer at another site. Our data support findings from previous epidemiologic and animal studies that suggest antidepressants may reduce the risk of colorectal cancer. Future studies with larger sample sizes should further examine individual drugs as well as dose, duration and recency of use.
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Affiliation(s)
- Jessica Chubak
- Group Health Research Institute, Group Health, Seattle, WA 98101-1448, USA.
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McNamara YM, Cloonan SM, Knox AJS, Keating JJ, Butler SG, Peters GH, Meegan MJ, Williams DC. Synthesis and serotonin transporter activity of 1,3-bis(aryl)-2-nitro-1-propenes as a new class of anticancer agents. Bioorg Med Chem 2010; 19:1328-48. [PMID: 21227702 DOI: 10.1016/j.bmc.2010.11.054] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Revised: 11/22/2010] [Accepted: 11/23/2010] [Indexed: 11/18/2022]
Abstract
Structural derivatives of 4-MTA, an illegal amphetamine analogue have been previously shown to have anticancer effects in vitro. In this study we report the synthesis of a series of novel 1,3-bis(aryl)-2-nitro-1-propene derivatives related in structure to 4-MTA. A number of these compounds containing a classic nitrostyrene structure are shown to have antiproliferative activities in vitro in a range of malignant cell lines, particularly against Burkitt's lymphoma derived cell lines, whilst having no effect on 'normal' peripheral blood mononuclear cells. Such effects appear to be independent of the serotonin transporter, a high affinity target for amphetamines and independent of protein tyrosine phosphatases and tubulin dynamics both of which have been previously associated with nitrostyrene-induced cell death. We demonstrate that a number of these compounds induce caspase activation, PARP cleavage, chromatin condensation and membrane blebbing in a Burkitt's lymphoma derived cell line, consistent with these compounds inducing apoptosis in vitro. Although no specific target has yet been identified for the action of these compounds, the cell death elicited is potent, selective and worthy of further investigation.
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Affiliation(s)
- Yvonne M McNamara
- School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Ireland
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Abstract
Background: Several studies suggest links between cancer and tricyclic antidepressant use. Methods: A case–control study using the General Practice Research Database examined whether previous tricyclic usage was associated with reduced incidence of brain (with glioma as a sub-category), breast, colorectal, lung and prostate cancers. Conditional logistic regression adjusted for age, gender, general practice, depression, smoking, body mass index, alcohol use and non-steroidal anti-inflammatory drug use. Results: A total of 31 953 cancers were identified, each matched with up to two controls. We found a statistically significant reduction in tricyclic prescriptions compared with controls in glioma (odds ratio (OR) =0.59, 95% confidence interval (CI)=0.42–0.81) and colorectal cancer patients (OR=0.84, CI=0.75–0.94). These effects were dose-dependent (P-values for trend, glioma=0.0005, colorectal=0.001) and time-dependant (P-values for trend glioma=0.0005, colorectal=0.0086). The effects were cancer-type specific, with lung, breast and prostate cancers largely unaffected by antidepressant use. Conclusion: The biologically plausible, specific and dose- and time-dependant inverse association that we have found suggests that tricyclics may have potential for prevention of both colorectal cancer and glioma.
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Cronin-Fenton DP, Riis AH, Lash TL, Dalton SO, Friis S, Robertson D, Sørensen HT. Antidepressant use and colorectal cancer risk: a Danish population-based case-control study. Br J Cancer 2010; 104:188-92. [PMID: 20877356 PMCID: PMC3039807 DOI: 10.1038/sj.bjc.6605911] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Background: Earlier research suggests that use of selective serotonin reuptake inhibitors (SSRIs), but not tricyclic antidepressants (TCAs), reduces the risk of colorectal cancer (CRC). Methods: We conducted a population-based case–control study to investigate the association between antidepressant use and CRC risk. Cases were diagnosed with a first primary CRC from 1991 through 2008. We selected 10 population controls matched to cases on sex, birth year, and residence from the Danish Civil Registration System using risk-set sampling. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) associating antidepressant use with colorectal cancer occurrence, controlling for potential confounders. Results: The study included 9979 cases and 99 790 controls. We found no notable reduction in CRC risk in ever users (⩾2 prescriptions) of TCAs (OR=0.94; 95% CI: 0.84, 1.05), SSRIs (OR=0.97; 95% CI: 0.90, 1.05), or other antidepressants (OR=0.95; 95% CI: 0.83, 1.07). Associations for recent and former use of antidepressants were also near null. Intensity of antidepressant use (number of pills divided by total duration of use), regardless of duration, was not associated with CRC risk. Conclusions: We found no evidence that antidepressant use substantially reduces the risk of colorectal cancer.
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Affiliation(s)
- D P Cronin-Fenton
- Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45, 8200, Aarhus N, Denmark.
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Ma J, Qiu Y, Yang L, Peng L, Xia Z, Hou LN, Fang C, Qi H, Chen HZ. Desipramine induces apoptosis in rat glioma cells via endoplasmic reticulum stress-dependent CHOP pathway. J Neurooncol 2010; 101:41-8. [PMID: 20549303 DOI: 10.1007/s11060-010-0237-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Accepted: 05/16/2010] [Indexed: 02/07/2023]
Abstract
Various antidepressants, mainly tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have exhibited potent anticancer properties in different cancer cell types. In the present study, desipramine (DMI), a representative of TCAs, was examined with respect to its apoptosis-inducing activity in rat C6 glioma cells and the underlying mechanism of action. DMI induced typical apoptotic morphology of chromatin condensation in rat glioma C6 cells and activated intracellular caspase 9 and caspase 3 with no change in mitochondrial membrane potential. Simultaneously, DMI significantly elevated expression of endoplasmic reticulum stress regulator CHOP/GADD153 and its targeting molecule GADD34. However, knockdown of CHOP by CHOP-specific short interfering RNA (siRNA) could decrease the activity of intracellular caspase 3 and the cytotoxicity of DMI to C6 cells. These results revealed that the CHOP-dependent endoplasmic reticulum (ER) stress pathway is responsible for DMI-induced apoptosis in C6 cells.
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Affiliation(s)
- Jian Ma
- Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
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Cloonan SM, Williams DC. The antidepressants maprotiline and fluoxetine induce Type II autophagic cell death in drug-resistant Burkitt's lymphoma. Int J Cancer 2010; 128:1712-23. [PMID: 20503272 DOI: 10.1002/ijc.25477] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Accepted: 05/12/2010] [Indexed: 12/15/2022]
Abstract
Resistance to chemotherapy is a major obstacle for the success of cancer therapy and is most commonly attributed to the inability of cancer cells to die by apoptosis, the archetypal programed cell death (PCD) response. The development of anticancer drugs that can overcome this resistance to apoptosis and induce other forms of cell death is therefore paramount for efficient cancer therapy. We report that the antidepressants maprotiline and fluoxetine induce autophagic PCD in the chemoresistant Burkitt's lymphoma (BL) cell line DG-75, which does not involve caspases, DNA fragmentation or PARP cleavage, but is associated with the development of cytoplasmic vacuoles, all consistent with an autophagic mode of PCD. Autophagic PCD was confirmed by transmission electron microscopy, upregulation of Beclin-I and the extent of PCD being reduced by the autophagic inhibitor 3-MA. In contrast, these compounds induced apoptotic PCD in the biopsy-like chemosensitive BL MUTU-I cell line. We provide evidence that the chemoresistant DG-75 cells do not express the proapoptotic Bcl-2 proteins Bax and Bak, show diminished levels of stored intracellular calcium and display shortened rod-like mitochondria, all of which are known to be associated with a defective "apoptotic" response in cancer cells. PCD in the two cell lines has different Ca(2+) responses to maprotiline and fluoxetine, which may also account for their differential PCD responses. Our study, therefore, supports a new mechanistic role for maprotiline and fluoxetine as novel proautophagic agents in the treatment of resistant BL, and thus an alternative therapeutic application for these compounds.
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Affiliation(s)
- Suzanne M Cloonan
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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