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Ma Y, He J, Li CY, Liu FB, Wang YG, Song FJ. Effect of antidepressants use on Cancer morbidity and mortality: A propensity score matched longitudinal cohort study. J Affect Disord 2025; 387:119554. [PMID: 40449745 DOI: 10.1016/j.jad.2025.119554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 05/14/2025] [Accepted: 05/28/2025] [Indexed: 06/03/2025]
Abstract
OBJECTIVE To investigate the association between antidepressant use and cancer risk in a large prospective cohort. METHODS A prospective cohort study involving participants without cancer or cardiovascular disease at baseline in the UK Biobank. Antidepressant users were matched to non-users using propensity score matching (PSM). The primary outcomes included overall cancer morbidity and mortality, with site-specific cancer morbidity as a secondary outcome. RESULTS The median follow-up was 13.6 years. Of the 421,529 participants, 26,796 were antidepressant users, and 394,733 were non-users. After 1:1 PSM, 26,372 matched pairs were identified. Antidepressant use was associated with a reduced risk of overall cancer morbidity (HR 0.83, 95 % CI 0.79-0.88), particularly for CRC (HR 0.75, 95 % CI 0.65-0.86), and a lower risk of cancer-related mortality (HR 0.91, 95 % CI 0.84-0.99) compared to nonusers. Among antidepressant subtypes, selective serotonin reuptake inhibitors (SSRIs) were associated with a lower risk of overall cancer morbidity, especially fluoxetine, citalopram, and sertraline. SSRIs were also associated with a reduced risk of cancer-related mortality, particularly fluoxetine and citalopram. However, tricyclic antidepressants (TCAs) were linked to an increased risk of cancer-related mortality (HR 1.19, 95 % CI 1.07-1.32), especially for amitriptyline. CONCLUSION The use of antidepressants, particularly SSRIs, was associated with a lower risk of cancer morbidity and mortality, whereas the use of TCAs, such as amitriptyline, was linked to an increased risk of cancer-related mortality. Although causal relationships cannot be established, these findings should be interpreted with caution and warrant further investigation.
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Affiliation(s)
- Yue Ma
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States
| | - Jing He
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Chen-Yang Li
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Fu-Bin Liu
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Yao-Gang Wang
- School of Public Health, Tianjin Medical University, Tianjin, China; School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Integrative Medicine, Public Health Science and Engineering College, Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Institute of Health Data Science at Peking University, Peking University, Beijing, China.
| | - Feng-Ju Song
- Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
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Liu ZQ, Ciudad MT, McGaha TL. New insights into tryptophan metabolism in cancer. Trends Cancer 2025:S2405-8033(25)00076-7. [PMID: 40274457 DOI: 10.1016/j.trecan.2025.03.008] [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: 02/01/2025] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/26/2025]
Abstract
Tryptophan (Trp) is an essential amino acid and key intermediate in a range of biological processes. Early studies identified altered Trp utilization in cancer cells favoring cancer survival and growth. Seminal findings linking Trp metabolism and suppression of immunity led to an explosion of interest ultimately culminating in clinical trials targeting these pathways in melanoma. The failure of these trials led to a clinical retreat in this approach; however, recent insights into the complex interplay of the various Trp circuits and between tumor cells, immune cells, and the microbiota have shown that reconsideration of Trp metabolism is needed. Here, we discuss recent developments in our understanding of Trp metabolism and apparent contradictions in the field. We also discuss adaptations that occur when Trp pathways are manipulated, which may impact therapy responses.
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Affiliation(s)
- Zhe Qi Liu
- Tumor Immunotherapy Program Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - M Teresa Ciudad
- Tumor Immunotherapy Program Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Tracy L McGaha
- Tumor Immunotherapy Program Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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Li Y, Yang SY, Zhang YR, Wang Y. Decoding the neuroimmune axis in colorectal cancer: From neural circuitry to therapeutic innovation. Cytokine Growth Factor Rev 2025:S1359-6101(25)00044-9. [PMID: 40274426 DOI: 10.1016/j.cytogfr.2025.04.001] [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: 04/05/2025] [Revised: 04/15/2025] [Accepted: 04/15/2025] [Indexed: 04/26/2025]
Abstract
The nervous and immune systems are two major components that maintain body homeostasis, with their functional roles often overlapping significantly. Both systems are capable of identifying, integrating, and organizing responsive reactions to various external stimuli. The gut, referred to as the "second brain" and the largest immune organ in the body, serves as the most frequent focal site for neuroimmune interactions. Colorectal cancer (CRC), as the predominant solid tumor arising in this neuroimmune-rich microenvironment, remains understudied through the lens of neuroimmune regulatory mechanisms. This review systematically synthesizes current evidence to elucidate the neuroimmune axis in CRC pathogenesis, with particular emphasis on neuroimmune crosstalk-mediated remodeling of tumor immunity. We comprehensively catalog the immunomodulatory effects exerted by principal neuroregulatory mediators, categorized as: (1) neurotransmitters (glutamate, glutamine, γ-aminobutyric acid, epinephrine, norepinephrine, dopamine, serotonin, acetylcholine, and gaseous signaling molecules); (2) neuropeptides (substance P, calcitonin gene-related peptide, vasoactive intestinal peptide); and (3) neurotrophic factors. Furthermore, we critically evaluate the translational prospects and therapeutic challenges of targeting neuroimmune pathways and propose strategic priorities and research focuses for advancing the development of neuroimmune interaction-related therapeutic approaches in CRC.
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Affiliation(s)
- Ying Li
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Sheng-Ya Yang
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ying-Ru Zhang
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The Second Clinical Medical College of Guizhou University of Traditional Chinese Medicine, Guizhou 550003, China.
| | - Yan Wang
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The Second Clinical Medical College of Guizhou University of Traditional Chinese Medicine, Guizhou 550003, China.
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Jennemann R, Volz M, Frias-Soler RC, Schulze A, Richter K, Kaden S, Sandhoff R. Glucosylceramide Synthase Inhibition in Combination with Aripiprazole Sensitizes Hepatocellular Cancer Cells to Sorafenib and Doxorubicin. Int J Mol Sci 2024; 26:304. [PMID: 39796160 PMCID: PMC11720485 DOI: 10.3390/ijms26010304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/28/2024] [Accepted: 12/29/2024] [Indexed: 01/13/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths due to its late diagnosis and restricted therapeutic options. Therefore, the search for appropriate alternatives to commonly applied therapies remains an area of high clinical need. Here we investigated the therapeutic potential of the glucosylceramide synthase (GCS) inhibitor Genz-123346 and the cationic amphiphilic drug aripiprazole on the inhibition of Huh7 and Hepa 1-6 hepatocellular cancer cell and tumor microsphere growth. Single and combinatorial treatments with both drugs at 5 µM concentration led to efficient cell cycle arrest, reduced expression of cyclins A and E, increased lipid storage in lysosomal compartments, accompanied by increased uptake of lysotracker, and elevated expression of the autophagy marker Lc3 II. Both drugs affected mitochondrial function, indicated by altered mitotracker uptake and impaired mitochondrial respiration. Aripiprazole in monotherapy, or even more pronounced in combination with Genz, also potentiated the effect of the cytostatic drugs sorafenib and doxorubicin on tumor cell- and tumor spheroid-growth inhibition. Targeting GCS with Genz with the parallel application of cationic amphiphilic drugs such as aripiprazole in combination with cytostatic drugs may thus represent a potent therapeutic approach in the treatment of HCC and potentially other cancer types.
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Affiliation(s)
- Richard Jennemann
- Lipid Pathobiochemistry Group, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany (R.S.)
| | - Martina Volz
- Lipid Pathobiochemistry Group, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany (R.S.)
| | - Roberto Carlos Frias-Soler
- Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
- Institute of Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany
| | - Almut Schulze
- Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
| | - Karsten Richter
- Core Facility Electron Microscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Sylvia Kaden
- Core Facility Electron Microscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Roger Sandhoff
- Lipid Pathobiochemistry Group, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany (R.S.)
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Hsu TW, Tsai SJ, Chen TJ, Chen MH, Liang CS. Exposure to Psychotropic Drugs and Colorectal Cancer Risk in Patients with Affective Disorder: A Nested Case-Control Study. PHARMACOPSYCHIATRY 2024. [PMID: 39689872 DOI: 10.1055/a-2479-9430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
BACKGROUND This study aimed to assess the association between the risk of colorectal cancer (CRC) and exposure to mood stabilizers, antidepressants, and antipsychotics in patients with affective disorders. METHODS This nested case-control study used data from the National Health Insurance Database of Taiwan collected between 2001 and 2011. All participants in this study had affective disorders. Then, 1209 patients with CRC and 1:10 matched controls were identified based on their demographic and clinical characteristics. A logistic regression model adjusted for demographic and clinical characteristics was used to determine the risk of developing CRC after exposure to psychotropic drugs. RESULTS Among patients with affective disorders, exposure to mood stabilizers (reported as odds ratio; 95% confidence interval; 0.75; 0.57-0.98), antidepressants (0.83; 0.70-0.97), second-generation antipsychotics (0.67; 0.52-0.86), and first-generation antipsychotics (0.65; 0.52-0.81) were associated with a reduced risk of CRC compared to patients who were not exposed. When considering specific drugs, carbamazepine (0.34; 0.12-0.95), valproic acid (0.66; 0.46-0.95), gabapentin (0.44; 0.20-0.99), fluoxetine (0.82; 0.68-0.99), paroxetine (0.63; 0.45-0.87), and venlafaxine (0.72; 0.55-0.95) were associated with a lower risk of CRC. CONCLUSION Exposure to psychotropic drugs in patients with affective disorders is associated with a lower risk of CRC compared to those who were not exposed. Although the causal relationship between psychotropic drug exposure and reduced risk of CRC could not be inferred directly, these findings may help clinicians and patients in clinical decision-making.
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Affiliation(s)
- Tien-Wei Hsu
- Department of Psychiatry, E-Da Dachang Hospital, I-Shou University, Kaohsiung, Taiwan
- Department of Psychiatry, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Psychiatry, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tzeng-Ji Chen
- Department of Family Medicine, Taipei Veterans General Hospital, Hsinchu Branch, Hsinchu, Taiwan
- Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan
| | - Mu-Hong Chen
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Psychiatry, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Sung Liang
- Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Psychiatry, National Defense Medical Center, Taipei, Taiwan
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Yan ZW, Liu YN, Xu Q, Yuan Y. Current trends and hotspots of depressive disorders with colorectal cancer: A bibliometric and visual study. World J Gastrointest Oncol 2024; 16:3687-3704. [PMID: 39171183 PMCID: PMC11334043 DOI: 10.4251/wjgo.v16.i8.3687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/26/2024] [Accepted: 06/17/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Depression is strongly associated with colorectal cancer (CRC). Few bibliometric analyses have systematically summarized the research focus and recent progress in this field. AIM To determine the research status and hotspots by bibliometric analysis of relevant publications on the relationship between CRC and depression. METHODS Articles on depression in CRC patients were collected from the Web of Science Core Collection. CiteSpace and VOSviewer software were used to visualize bibliometric networks. RESULTS From 2001 to 2022, Supportive Care in Cancer, the United States, Tilburg University, and Mols were the most productive and influential journal, country, institution, and author name. Co-occurrence cluster analysis of keywords placed quality of life, anxiety, and psychological stress in the center of the visual network diagram. Further clustering was performed for the clusters with studies of the relevant mechanism of action, which showed that: (1) Cytokines have a role essential for the occurrence and development of depressive disorders in CRC; (2) MicroRNAs have a role essential for the development of depressive disorders in CRC; (3) Some anticancer drugs have pro-depressant activity; and (4) Selective serotonin reuptake inhibitors have both antitumor and antidepressant activity. CONCLUSION Life quality and psychological nursing of the cancer population were key topics. The roles of cytokines and microRNAs, the pro-depression activity of anticancer drugs and their antitumor properties deserve in-depth study.
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Affiliation(s)
- Zi-Wei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ying-Nan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Chen L, Huang S, Wu X, He W, Song M. Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities. Clin Transl Med 2024; 14:e1750. [PMID: 38943041 PMCID: PMC11213692 DOI: 10.1002/ctm2.1750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/09/2024] [Accepted: 06/13/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Serotonin (5-hydroxytryptamine) is a multifunctional bioamine serving as a neurotransmitter, peripheral hormone and mitogen in the vertebrate system. It has pleiotropic activities in central nervous system and gastrointestinal function via an orchestrated action of serotonergic elements, particularly serotonin receptor-mediated signalling cascades. The mitogenic properties of serotonin have garnered recognition for years and have been exploited for repurposing serotonergic-targeted drugs in cancer therapy. However, emerging conflicting findings necessitate a more comprehensive elucidation of serotonin's role in cancer pathogenesis. MAIN BODY AND CONCLUSION Here, we provide an overview of the biosynthesis, metabolism and action modes of serotonin. We summarise our current knowledge regarding the effects of the peripheral serotonergic system on tumourigenesis, with a specific emphasis on its immunomodulatory activities in human cancers. We also discuss the dual roles of serotonin in tumour pathogenesis and elucidate the potential of serotonergic drugs, some of which display favourable safety profiles and impressive efficacy in clinical trials, as a promising avenue in cancer treatment. KEY POINTS Primary synthesis and metabolic routes of peripheral 5-hydroxytryptamine in the gastrointestinal tract. Advanced research has established a strong association between the serotonergic components and carcinogenic mechanisms. The interplay between serotonergic signalling and the immune system within the tumour microenvironment orchestrates antitumour immune responses. Serotonergic-targeted drugs offer valuable clinical options for cancer therapy.
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Affiliation(s)
- Lulu Chen
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Sun Yat‐Sen UniversitySun Yat‐Sen UniversityGuangzhouChina
- Institute of Precision MedicineThe First Affiliated Hospital of Sun Yat‐Sen UniversitySun Yat‐Sen UniversityGuangzhouChina
| | - Shuting Huang
- School of Public HealthSun Yat‐Sen UniversityGuangzhouChina
| | - Xiaoxue Wu
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Sun Yat‐Sen UniversitySun Yat‐Sen UniversityGuangzhouChina
| | - Weiling He
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Sun Yat‐Sen UniversitySun Yat‐Sen UniversityGuangzhouChina
- Department of Gastrointestinal SurgeryXiang'an Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamenChina
| | - Mei Song
- Institute of Precision MedicineThe First Affiliated Hospital of Sun Yat‐Sen UniversitySun Yat‐Sen UniversityGuangzhouChina
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Kadasah SF, Alqahtani AMS, Alkhammash A, Radwan MO. Beyond Psychotropic: Potential Repurposing of Fluoxetine toward Cancer Therapy. Int J Mol Sci 2024; 25:6314. [PMID: 38928021 PMCID: PMC11203592 DOI: 10.3390/ijms25126314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/05/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), were studied for their potential application in different diseases, especially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from the SSRIs class for the treatment of several neuropsychiatric disorders with a favorable safety profile. FLX exhibited different oncolytic effects via mechanisms distinct from its main serotonergic activity. Taking advantage of its ability to rapidly penetrate the blood-brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of the literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers, highlighting the multifaceted activities of FLX and its ability to interrupt cancer proliferation via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX onto carriers to enhance its safety and efficacy on cancer cells. This is the first review article extensively summarizing all previous FLX repurposing studies for the management of cancer.
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Affiliation(s)
- Sultan F. Kadasah
- Department of Biology, Faculty of Science, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
| | - Abdulaziz M. S. Alqahtani
- Department of Biology, Faculty of Science, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
| | - Abdullah Alkhammash
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
| | - Mohamed O. Radwan
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan
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Salvi PS, Shaughnessy MP, Sumigray KD, Cowles RA. Antibiotic-induced microbial depletion enhances murine small intestinal epithelial growth in a serotonin-dependent manner. Am J Physiol Gastrointest Liver Physiol 2023; 325:G80-G91. [PMID: 37158470 DOI: 10.1152/ajpgi.00113.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 01/06/2023] [Accepted: 01/28/2023] [Indexed: 05/10/2023]
Abstract
Regulation of small intestinal epithelial growth by endogenous and environmental factors is critical for intestinal homeostasis and recovery from insults. Depletion of the intestinal microbiome increases epithelial proliferation in small intestinal crypts, similar to the effects observed in animal models of serotonin potentiation. Based on prior evidence that the microbiome modulates serotonin activity, we hypothesized that microbial depletion-induced epithelial proliferation is dependent on host serotonin activity. A mouse model of antibiotic-induced microbial depletion (AIMD) was employed. Serotonin potentiation was achieved through either genetic knockout of the serotonin transporter (SERT) or pharmacological SERT inhibition, and inhibition of serotonin synthesis was achieved with para-chlorophenylalanine. AIMD and serotonin potentiation increased intestinal villus height and crypt proliferation in an additive manner, but the epithelial proliferation observed after AIMD was blocked in the absence of endogenous serotonin. Using Lgr5-EGFP-reporter mice, we evaluated intestinal stem cell (ISC) quantity and proliferation. AIMD increased the number of ISCs per crypt and ISC proliferation compared with controls, and changes in ISC number and proliferation were dependent on the presence of host serotonin. Furthermore, Western blotting demonstrated that AIMD reduced epithelial SERT protein expression compared with controls. In conclusion, host serotonin activity is necessary for microbial depletion-associated changes in villus height and ISC proliferation in crypts, and microbial depletion produces a functional serotonin-potentiated state through reduced SERT protein expression. These findings provide an understanding of how changes to the microbiome contribute to intestinal pathology and can be applied therapeutically.NEW & NOTEWORTHY Antibiotic-induced microbial depletion of the murine small intestine results in a state of potentiated serotonin activity through reduced epithelial expression of the serotonin transporter. Specifically, serotonin-dependent mechanisms lead to increased intestinal surface area and intestinal stem cell proliferation. Furthermore, the absence of endogenous serotonin leads to blunting of small intestinal villi, suggesting that serotonin signaling is required for epithelial homeostasis.
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Affiliation(s)
- Pooja S Salvi
- Division of Pediatric Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Matthew P Shaughnessy
- Division of Pediatric Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Kaelyn D Sumigray
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Robert A Cowles
- Division of Pediatric Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States
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Zhang H, Han J, Zhang J, Miao J, Li F, Tang K, Zhou K, Duan B, Li W, Cheng J, Sun Y, Hou N, Huang C. Venlafaxine antagonizes the noradrenaline-promoted colon cancer progression by inhibiting the norepinephrine transporter. Cell Death Discov 2023; 9:152. [PMID: 37156838 PMCID: PMC10167232 DOI: 10.1038/s41420-023-01447-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 04/13/2023] [Accepted: 04/24/2023] [Indexed: 05/10/2023] Open
Abstract
Epidemiological studies have demonstrated that the use of antidepressants is associated with a decreased risk of colorectal cancer (CRC); however, the mechanisms behind this association are yet unknown. Adrenergic system contributes to the stress-related tumor progression, with norepinephrine (NE) mainly secreted from adrenergic nerve fibers. Norepinephrine serotonin reuptake inhibitors are successfully used antidepressants. This study demonstrates that a widely used antidepressant venlafaxine (VEN) antagonizes NE-promoted colon cancer in vivo and in vitro. Bioinformatic analysis suggested that NE transporter (NET, SLC6A2), a target of VEN, was closely associated with the prognosis of clinical patients with CRC. In addition, the knockdown of NET antagonized the effect of NE. The NET-protein phosphatase 2 scaffold subunit alpha/phosphorylated Akt/vascular endothelial growth factor pathway partially mediates the antagonizing effect of VEN on NE's actions in colon cancer cells. These were also confirmed by in vivo experiments. Our findings revealed for the first time that, in addition to its primary function as a transporter, NET also promotes NE-enhanced colon cancer cell proliferation, tumor angiogenesis, and tumor growth. This provides direct experimental and mechanistic evidence for the use of antidepressant VEN in the treatment of CRC and a therapeutic potential for repurposing existing drugs as an anti-cancer approach to improve the prognosis of patients with CRC.
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Affiliation(s)
- Huahua Zhang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, China
| | - Jiming Han
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, China
| | - Jing Zhang
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, China
| | - Jiyu Miao
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Department of Hematology, The Second Affiliated Hospital of Xian Jiaotong University, Xi'an, 710004, China
| | - Fang Li
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Kaijie Tang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Kai Zhou
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Baojun Duan
- Department of Medical Oncology of Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Wen Li
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Jing Cheng
- 3201 Affiliated Hospital of Medical College of Xi'an Jiaotong University, Hanzhong, 723000, China
| | - Ying Sun
- Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Ni Hou
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
- Institute of Genetics and Developmental Biology, Xi'an Jiaotong University, Xi'an, 710061, China.
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Chen Huang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
- Institute of Genetics and Developmental Biology, Xi'an Jiaotong University, Xi'an, 710061, China.
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an, 710061, China.
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11
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Yu H, Qu T, Yang J, Dai Q. Serotonin acts through YAP to promote cell proliferation: mechanism and implication in colorectal cancer progression. Cell Commun Signal 2023; 21:75. [PMID: 37046308 PMCID: PMC10100184 DOI: 10.1186/s12964-023-01096-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 03/07/2023] [Indexed: 04/14/2023] Open
Abstract
Serotonin, also known as 5-hydroxytryptamine (5-HT), is a key messenger that mediates several central and peripheral functions in the human body. Emerging evidence indicates that serotonin is critical in tumorigenesis, but its role in colorectal cancer remains elusive. Herein, we report that serotonin transporter (SERT) transports serotonin into colorectal cancer cells, enhancing Yes-associated protein (YAP) expression and promoting in vitro and in vivo colon cancer cell growth. Once within the cells, transglutaminase 2 (TG2) mediates RhoA serotonylated and activates RhoA-ROCK1/2 signalling to upregulate YAP expression in SW480 and SW1116 cells. Blocking SERT with citalopram reversed the serotonin-induced YAP expression and cell proliferation, inhibiting serotonin's effects on tumour formation in mice. Moreover, SERT expression was correlated with YAP in pathological human colorectal cancer samples and the levels of 5-HT were highly significant in the serum of patients with colorectal cancer. Together, our findings suggested that serotonin enters cells via SERT to activate RhoA/ROCK/YAP signalling to promote colon cancer carcinogenesis. Consequently, targeting serotonin-SERT-YAP axis may be a potential therapeutic strategy for colorectal cancer. Video abstract.
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Affiliation(s)
- Huangfei Yu
- Department of Oncology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China.
- Clinical Cancer Center of Zunyi, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China.
- Scientific Research Center, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China.
| | - Tianyin Qu
- Department of Oncology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
- Clinical Cancer Center of Zunyi, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
- Scientific Research Center, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
| | - Jinlan Yang
- Department of Oncology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
- Scientific Research Center, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
| | - Qing Dai
- Department of Oncology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
- Scientific Research Center, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
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12
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Nimal R, Nur Unal D, Erkmen C, Kurbanoglu S, Siddiq M, Eren G, Shah A, Uslu B. Elucidating the interaction of antidepressant drug paroxetine with ct-dsDNA: A comparative study by electrochemical, spectroscopic, and molecular docking approaches. Bioelectrochemistry 2023; 149:108285. [PMID: 36240548 DOI: 10.1016/j.bioelechem.2022.108285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 09/28/2022] [Accepted: 10/02/2022] [Indexed: 11/05/2022]
Abstract
This study is designed to investigate the interaction of phenylpiperidine derivative drug paroxetine, which is an effective serotonin reuptake inhibitor and biomolecules through electrochemical, fluorescence spectroscopy, and molecular docking methods. The interaction between paroxetine and biomolecules was investigated by differential pulse voltammetry according to the decrease in deoxyguanosine anodic oxidation signal of double-stranded calf thymus DNA. Fluorescence spectroscopy studies were performed by titrating paroxetine against double-stranded calf thymus DNA solution at four different temperatures. The fluorescent results showed that paroxetine had a great affinity to bind with double-stranded calf thymus DNA. Interaction studies demonstrate that paroxetine binds to double-stranded calf thymus DNA via intercalation binding mode, and the binding constant values were calculated as 7.24 × 104 M-1 and 1.52 × 104 M-1 at 25 °C, based on voltammetric and spectroscopic results, respectively. Moreover, with the aim of elucidating the interaction mechanism between paroxetine and double-stranded calf thymus DNA, electrochemical and fluorescence spectroscopy studies along with molecular docking analysis were made.
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Affiliation(s)
- Rafia Nimal
- Quaid-i-Azam University, Department of Chemistry, Islamabad 45320, Pakistan; Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06560 Ankara, Turkey
| | - Didem Nur Unal
- Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06560 Ankara, Turkey; Ankara University, The Graduate School of Health Sciences, Ankara 06110, Turkey
| | - Cem Erkmen
- Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06560 Ankara, Turkey; Ankara University, The Graduate School of Health Sciences, Ankara 06110, Turkey
| | - Sevinc Kurbanoglu
- Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06560 Ankara, Turkey
| | - Muhammad Siddiq
- Quaid-i-Azam University, Department of Chemistry, Islamabad 45320, Pakistan
| | - Gokcen Eren
- Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06330 Ankara, Turkey
| | - Afzal Shah
- Quaid-i-Azam University, Department of Chemistry, Islamabad 45320, Pakistan
| | - Bengi Uslu
- Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06560 Ankara, Turkey.
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13
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Synergistic Effects of the Combinational Use of Escitalopram Oxalate and 5-Fluorouracil on the Inhibition of Gastric Cancer SNU-1 Cells. Int J Mol Sci 2022; 23:ijms232416179. [PMID: 36555820 PMCID: PMC9781210 DOI: 10.3390/ijms232416179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/15/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Owing to its high recurrence rate, gastric cancer (GC) is the leading cause of tumor-related deaths worldwide. Besides surgical treatment, chemotherapy is the most commonly used treatment against GC. However, the adverse events associated with chemotherapy use limit its effectiveness in GC treatment. In this study, we investigated the effects of using combinations of low-dose 5-fluorouracil (5-FU; 0.001 and 0.01 mM) with different concentrations of escitalopram oxalate (0.01, 0.02, 0.06, and 0.2 mM) to evaluate whether the assessed combination would have synergistic effects on SNU-1 cell survival. 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.06 mM) administered over 24 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Moreover, 5-FU (0.001 mM) + escitalopram oxalate (0.02 or 0.06 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.02, 0.06, or 0.2 mM) administered over 48 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Compared with controls, SNU-1 cells treated with 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) exhibited significantly increased levels of annexin V staining, reactive oxygen species, cleaved poly (ADP-ribose) polymerase, and caspase-3 proteins. Furthermore, 5-FU (12 mg/kg) + escitalopram oxalate (12.5 mg/kg) significantly attenuated xenograft SNU-1 cell proliferation in nude mice. Our study is the first to report the synergistic effects of the combinational use of low-dose 5-FU and escitalopram oxalate on inhibiting SNU-1 cell proliferation. These findings may be indicative of an alternative option for GC treatment.
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14
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Use of Selective Serotonin Reuptake Inhibitors Is Associated with a Lower Risk of Colorectal Cancer among People with Family History. Cancers (Basel) 2022; 14:cancers14235905. [PMID: 36497383 PMCID: PMC9741129 DOI: 10.3390/cancers14235905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/27/2022] [Accepted: 11/28/2022] [Indexed: 12/02/2022] Open
Abstract
Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical and population-based evidence suggests that selective serotonin reuptake inhibitors (SSRIs) might play a role in preventing CRC. We performed a nationwide cohort study to explore whether the use of SSRIs could reduce CRC risk among individuals with family history. We identified individuals aged 50 and above who had one or more first-degree relatives diagnosed with CRC. A total of 38,617 incident SSRI users were identified and matched with 115,851 non-users, on a ratio of 1:3. The Cox regression model was used to calculate hazard ratios (HRs) and 95% CI confidence intervals (CIs). We found a significant negative association between SSRI use and the risk of CRC (adjusted HR, 0.77; 95% CI, 0.70-0.85). Restricted cubic spline regression showed a non-linear dose-responded relationship between SSRI use and CRC risk. The association was stronger in rectal cancer than colon cancer (adjusted HR, 0.73 vs. 0.79), and more pronounced in advanced-stage CRC than early-stage CRC (adjusted HR, 0.73 vs. 0.80). This population-based cohort study suggests that the use of SSRIs is associated with a reduced risk of CRC among individuals with a family history of CRC.
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15
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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: 9] [Impact Index Per Article: 3.0] [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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17
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Bhagavathula AS, Woolf B, Rahmani J, Vidyasagar K, Tesfaye W. Selective serotonin reuptake inhibitor use and the risk of hepatocellular carcinoma: a systematic review and dose-response analysis of cohort studies with one million participants. Eur J Clin Pharmacol 2022; 78:547-555. [PMID: 35039907 DOI: 10.1007/s00228-021-03264-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/09/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE Recent studies have suggested a lower risk of hepatocellular carcinoma (HCC) in patients receiving selective serotonin reuptake inhibitors (SSRIs). The current study aimed to provide an updated and comprehensive assessment of the association between SSRI use and development of HCC. METHODS This is a systematic review and meta-analysis of all observational studies published until June 2021. We comprehensively searched PubMed/Medline, Web of Science, and Embase to identify studies comparing SSRIs use with control in relation to the risk of HCC. We calculated pooled relative risks (RRs) and 95% confidence intervals (CIs) for the association between SSRI use and incident HCC risk using random-effects meta-analysis. A dose-response analysis was conducted to evaluate the HCC risk according to the defined daily dose (DDD) of SSRI use. RESULTS Eight observational studies, comprising 1,051,096 participants and 22,316 incidences of HCC, examining the association between SSRIs use and HCC risk, were included in the systematic review (adjusted RR: 0.66; 95% CI: 0.56-0.79; P ≤ 0.001). In subgroup analysis, the magnitude of benefit associated with SSRIs was significantly higher in patients with hepatitis infection (RR: 0.70, 95% CI: 0.51-0.95) than the general population (Pheterogeneity = 0.700). The dose-response analysis indicated strong inverse association between cumulative DDD of SSRI and risk of HCC (coefficient: - 0.0030; P = 0.002; R2 = 0.78). CONCLUSIONS The results of this review show that SSRI use was associated with a 34% lower risk of HCC, which tend to be dose dependent. Further prospective studies are warranted to confirm these observations across the spectrum of chronic liver disease and hepatitis infection.
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Affiliation(s)
- Akshaya Srikanth Bhagavathula
- Department of Social and Clinical Pharmacy, Faculty of Pharmacy at Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Benjamin Woolf
- Department of Psychological Sciences, University of Bristol, Bristol, BS8 1TH, UK
| | - Jamal Rahmani
- Department of Community Nutrition, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kota Vidyasagar
- Department of Pharmaceutical Sciences, University College of Pharmaceutical Sciences, Hanamkonda, 506009, Telangana, India
| | - Wubshet Tesfaye
- Health Research Institute, University of Canberra, Canberra, Australia.
- Sydney Pharmacy School, The University of Sydney, Sydney, NSW, Australia.
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18
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Baio R, Spiezia N, Marani C, Schettini M. Potential contribution of benzodiazepine abuse in the development of a bladder sarcomatoid carcinoma: A case report. Mol Clin Oncol 2021; 15:231. [PMID: 34584692 PMCID: PMC8461628 DOI: 10.3892/mco.2021.2394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 08/18/2021] [Indexed: 12/20/2022] Open
Abstract
Invasive urothelial carcinoma has a propensity for disparate differentiation and presentation of morphological variants. Sarcomatoid carcinoma (SaC) of the bladder is an extremely uncommon and aggressive variant of bladder cancer. An accurate diagnosis for this variant is necessary, but at times difficult. Immunohistochemistry can increase the diagnostic accuracy for SaC. The therapeutic approaches currently adopted for the treatment of SaC are similar to those used for the urothelial variant: Surgery, chemotherapy and radiation therapy. To date, however, there exists no standard treatment due to the lack of knowledge regarding the pathogenesis of SaC. Future research is required to focus on this rare histological tumor subtype in order to identify more effective treatment strategies. The present study reported an unusual case of bladder SaC in a woman aged 48 years, who was a non-smoker with a long history of benzodiazepine abuse. Although saving the patient's life was a priority, it was also essential to consider her subsequent quality of life. For that reason, the patient underwent a cystectomy with orthotopic neobladder reconstruction using ileum, followed by chemotherapy. At the 7 month follow-up, the patient was still alive, in complete remission and had normal bladder function. The present case report shows the potential contribution of benzodiazepine abuse in the development of a bladder sarcomatoid carcinoma, a rare variant of BC, whose early detection and accurate diagnosis are key to attaining satisfactory treatment outcomes and a favorable prognosis for patients.
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Affiliation(s)
- Raffaele Baio
- Department of Urology, University of Salerno, I-84081 Salerno, Italy
| | - Nicola Spiezia
- Department of Urology, Private Hospital ‘Lourdes Clinic’, I-80040 Naples, Italy
| | - Carla Marani
- Department of Anatomopathology, San Carlo Hospital of Nancy, I-00165 Rome, Italy
| | - Manlio Schettini
- Department of Urology, Private Hospital ‘Lourdes Clinic’, I-80040 Naples, Italy
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19
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Jennemann R, Volz M, Bestvater F, Schmidt C, Richter K, Kaden S, Müthing J, Gröne HJ, Sandhoff R. Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo. Int J Mol Sci 2021; 22:ijms221910539. [PMID: 34638879 PMCID: PMC8508865 DOI: 10.3390/ijms221910539] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/21/2021] [Accepted: 09/22/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in humans. At early stages CRC is treated by surgery and at advanced stages combined with chemotherapy. We examined here the potential effect of glucosylceramide synthase (GCS)-inhibition on CRC biology. GCS is the rate-limiting enzyme in the glycosphingolipid (GSL)-biosynthesis pathway and overexpressed in many human tumors. We suppressed GSL-biosynthesis using the GCS inhibitor Genz-123346 (Genz), NB-DNJ (Miglustat) or by genetic targeting of the GCS-encoding gene UDP-glucose-ceramide-glucosyltransferase- (UGCG). GCS-inhibition or GSL-depletion led to a marked arrest of the cell cycle in Lovo cells. UGCG silencing strongly also inhibited tumor spheroid growth in Lovo cells and moderately in HCT116 cells. MS/MS analysis demonstrated markedly elevated levels of sphingomyelin (SM) and phosphatidylcholine (PC) that occurred in a Genz-concentration dependent manner. Ultrastructural analysis of Genz-treated cells indicated multi-lamellar lipid storage in vesicular compartments. In mice, Genz lowered the incidence of experimentally induced colorectal tumors and in particular the growth of colorectal adenomas. These results highlight the potential for GCS-based inhibition in the treatment of CRC.
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Affiliation(s)
- Richard Jennemann
- Lipid Pathobiochemistry Group, German Cancer Research Center, 69120 Heidelberg, Germany; (M.V.); (R.S.)
- Correspondence:
| | - Martina Volz
- Lipid Pathobiochemistry Group, German Cancer Research Center, 69120 Heidelberg, Germany; (M.V.); (R.S.)
| | - Felix Bestvater
- Light Microscopy Facility, German Cancer Research Center, 69120 Heidelberg, Germany; (F.B.); (C.S.)
| | - Claudia Schmidt
- Light Microscopy Facility, German Cancer Research Center, 69120 Heidelberg, Germany; (F.B.); (C.S.)
| | - Karsten Richter
- Core Facility Electron Microscopy, German Cancer Research Center, 69120 Heidelberg, Germany; (K.R.); (S.K.)
| | - Sylvia Kaden
- Core Facility Electron Microscopy, German Cancer Research Center, 69120 Heidelberg, Germany; (K.R.); (S.K.)
| | - Johannes Müthing
- Institute for Hygiene, University of Münster, 48149 Münster, Germany;
| | - Hermann-Josef Gröne
- Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany;
- Institute of Pharmacology, University of Marburg, 35043 Marburg, Germany
| | - Roger Sandhoff
- Lipid Pathobiochemistry Group, German Cancer Research Center, 69120 Heidelberg, Germany; (M.V.); (R.S.)
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20
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Malard F, Jacquet E, Nhiri N, Sizun C, Chabrier A, Messaoudi S, Dejeu J, Betzi S, Zhang X, Thureau A, Lescop E. Revisiting the Molecular Interactions between the Tumor Protein TCTP and the Drugs Sertraline/Thioridazine. ChemMedChem 2021; 17:e202100528. [PMID: 34472703 DOI: 10.1002/cmdc.202100528] [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: 08/05/2021] [Indexed: 11/07/2022]
Abstract
TCTP protein is a pharmacological target in cancer and TCTP inhibitors such as sertraline have been evaluated in clinical trials. The direct interaction of TCTP with the drugs sertraline and thioridazine has been reported in vitro by SPR experiments to be in the ∼30-50 μM Kd range (Amson et al. Nature Med 2012), supporting a TCTP-dependent mode of action of the drugs on tumor cells. However, the molecular details of the interaction remain elusive although they are crucial to improve the efforts of on-going medicinal chemistry. In addition, TCTP can be phosphorylated by the Plk-1 kinase, which is indicative of poor prognosis in several cancers. The impact of phosphorylation on TCTP structure/dynamics and binding with therapeutical ligands remains unexplored. Here, we combined NMR, TSA, SPR, BLI and ITC techniques to probe the molecular interactions between TCTP with the drugs sertraline and thioridazine. We reveal that drug binding is much weaker than reported with an apparent ∼mM Kd and leads to protein destabilization that obscured the analysis of the published SPR data. We further demonstrate by NMR and SAXS that TCTP S46 phosphorylation does not promote tighter interaction between TCTP and sertraline. Accordingly, we question the supported model in which sertraline and thioridazine directly interact with isolated TCTP in tumor cells and discuss alternative modes of action for the drugs in light of current literature.
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Affiliation(s)
- Florian Malard
- Institut de Chimie des Substances Naturelles, CNRS, Université Paris-Saclay, 1 av. de la terrasse, 91198, Gif-sur-Yvette, France
| | - Eric Jacquet
- Institut de Chimie des Substances Naturelles, CNRS, Université Paris-Saclay, 1 av. de la terrasse, 91198, Gif-sur-Yvette, France
| | - Naima Nhiri
- Institut de Chimie des Substances Naturelles, CNRS, Université Paris-Saclay, 1 av. de la terrasse, 91198, Gif-sur-Yvette, France
| | - Christina Sizun
- Institut de Chimie des Substances Naturelles, CNRS, Université Paris-Saclay, 1 av. de la terrasse, 91198, Gif-sur-Yvette, France
| | - Amélie Chabrier
- Université Paris-Saclay, BioCIS, Faculté de Pharmacie, CNRS, 92290, Châtenay-Malabry, France
| | - Samir Messaoudi
- Université Paris-Saclay, BioCIS, Faculté de Pharmacie, CNRS, 92290, Châtenay-Malabry, France
| | - Jérôme Dejeu
- Univ. Grenoble Alpes, CNRS, DCM, 38000, Grenoble, France
| | - Stéphane Betzi
- Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS, Aix-Marseille Université, Inserm, Institut Paoli-Calmettes, 27 bd Lei Roure, 13273, Marseille CEDEX 9, France
| | - Xu Zhang
- Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS, Aix-Marseille Université, Inserm, Institut Paoli-Calmettes, 27 bd Lei Roure, 13273, Marseille CEDEX 9, France
| | | | - Ewen Lescop
- Institut de Chimie des Substances Naturelles, CNRS, Université Paris-Saclay, 1 av. de la terrasse, 91198, Gif-sur-Yvette, France
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21
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Sagara A, Nakata K, Matsumoto S, Guan W, Shinkawa T, Iwamoto C, Ikenaga N, Ohuchida K, Nakamura M. Repositioning of duloxetine to target pancreatic stellate cells. Oncol Lett 2021; 22:744. [PMID: 34466156 PMCID: PMC8387862 DOI: 10.3892/ol.2021.13005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/29/2021] [Indexed: 11/05/2022] Open
Abstract
Pancreatic cancer cells (PCCs) are surrounded by an abundant stroma, which is produced by pancreatic stellate cells (PSCs). PSCs promote tumor cell proliferation and invasion. The objective of the current study was to identify compounds that suppress PSC activation. Gene expression profiles of cancer-derived fibroblasts and normal fibroblasts were used, and the pathway analysis suggested altered pathways that were chosen for validation. It was found that the ‘neuroactive ligand-receptor interaction’ pathway from the Kyoto Encyclopedia of Genes and Genomes pathway analysis was one of the altered pathways. Several compounds related with this pathway were chosen, and changes in PSC activity were investigated using fluorescence staining of lipid droplets, reverse transcription-quantitative PCR, western blotting, and invasion and migration assays. Among these candidates, duloxetine, a serotonin-noradrenaline reuptake inhibitor, was found to suppress PSC activation and disrupt tumor-stromal interaction. Thus, duloxetine may be a potential drug for suppressing PSC activation and pancreatic cancer growth.
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Affiliation(s)
- Akiko Sagara
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kohei Nakata
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Sokichi Matsumoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Weiyu Guan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Tomohiko Shinkawa
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Chika Iwamoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Naoki Ikenaga
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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22
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Zhang H, Xu H, Tang Q, Bi F. The selective serotonin reuptake inhibitors enhance the cytotoxicity of sorafenib in hepatocellular carcinoma cells. Anticancer Drugs 2021; 32:793-801. [PMID: 33675613 DOI: 10.1097/cad.0000000000001067] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Sertraline and fluoxetine are the two most commonly used selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. Accumulating evidence has revealed that SSRIs can reduce the risk of hepatocellular carcinoma (HCC), but their therapeutic effects in HCC have not yet been elucidated. Previous studies have reported that sertraline and fluoxetine can suppress the growth of gastric carcinoma, melanoma and nonsmall cell lung cancers by inhibiting the mammalian target rapamycin (mTOR) activity. In this study, we found that sertraline and fluoxetine blocked the protein kinase B (AKT)/mTOR pathway and suppressed the growth of HCC cells in vitro, in xenografts and in diethylnitrosamine/carbon tetrachloride (DEN/CCL4)-induced primary liver mouse model. Sertraline and fluoxetine can synergize with sorafenib, the first approved standard therapy for advanced HCC, to inhibit the viability of HCC cells in vitro and in vivo. In addition, the combination of sorafenib and SSRIs synergistically inhibited the effects of the AKT/mTOR pathway. These results reveal novel therapeutic effects of a combination of SSRIs and sorafenib in HCC.
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Affiliation(s)
- Huan Zhang
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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23
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Combined Use of Aspirin and Selective Serotonin Reuptake Inhibitors Is Associated With Lower Risk of Colorectal Cancer: A Nested Case-Control Study. Am J Gastroenterol 2021; 116:1313-1321. [PMID: 33661146 DOI: 10.14309/ajg.0000000000001192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 01/22/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Chemoprevention against colorectal cancer (CRC) is greatly needed. As the development of CRC involves multiple dysfunctional pathways, it is thus reasonable to combine some agents that address several pathways to achieve better chemoprotection. We aimed to explore whether the use of aspirin and selective serotonin reuptake inhibitors (SSRIs)-either as monotherapy or combined-can have a clinical benefit against CRC. METHODS We performed a nested case-control study using nationwide Swedish registers. We recruited 24,786 CRC cases and randomly matched to 74,358 controls conditional on birth year and sex using incidence-density sampling. The conditional logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Additive interaction was calculated as the relative excess risk for interaction, and multiplicative interaction was calculated by including a product term in the regression model. RESULTS Both aspirin and SSRIs monotherapy were negatively associated with CRC risk, but the combined use of aspirin and SSRIs was associated with an even lower CRC risk (adjusted OR, 0.77, 95% CI, 0.67-0.89) than aspirin monotherapy (adjusted OR, 0.91, 95% CI, 0.87-0.97) or SSRI monotherapy (adjusted OR, 0.93, 95% CI, 0.86-1.00). A significant interaction was observed at the additive scale with a relative excess risk for interaction of -0.07 (P < 0.001), whereas no interaction was noted on the interactive scale. The inverse associations of CRC with aspirin and SSRIs showed a dose-dependent pattern. DISCUSSION This study suggests that the use of aspirin and SSRIs-either as monotherapy or combined-was associated with a reduced risk of CRC. The stronger chemoprevention of combined use of aspirin and SSRIs is innovative and calls for further studies to confirm the underlying mechanisms and the plausibility of clinical recommendation.
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24
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Antoszczak M, Markowska A, Markowska J, Huczyński A. Antidepressants and Antipsychotic Agents as Repurposable Oncological Drug Candidates. Curr Med Chem 2021; 28:2137-2174. [PMID: 32895037 DOI: 10.2174/0929867327666200907141452] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/26/2020] [Accepted: 06/10/2020] [Indexed: 11/22/2022]
Abstract
Drug repurposing, also known as drug repositioning/reprofiling, is a relatively new strategy for the identification of alternative uses of well-known therapeutics that are outside the scope of their original medical indications. Such an approach might entail a number of advantages compared to standard de novo drug development, including less time needed to introduce the drug to the market, and lower costs. The group of compounds that could be considered as promising candidates for repurposing in oncology include the central nervous system drugs, especially selected antidepressant and antipsychotic agents. In this article, we provide an overview of some antidepressants (citalopram, fluoxetine, paroxetine, sertraline) and antipsychotics (chlorpromazine, pimozide, thioridazine, trifluoperazine) that have the potential to be repurposed as novel chemotherapeutics in cancer treatment, as they have been found to exhibit preventive and/or therapeutic action in cancer patients. Nevertheless, although drug repurposing seems to be an attractive strategy to search for oncological drugs, we would like to clearly indicate that it should not replace the search for new lead structures, but only complement de novo drug development.
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Affiliation(s)
- Michał Antoszczak
- Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Poznan, Poland
| | - Anna Markowska
- \Department of Perinatology and Women's Diseases, Poznań University of Medical Sciences, Poznan, Poland
| | - Janina Markowska
- Department of Oncology, Poznań University of Medical Sciences, Poznan, Poland
| | - Adam Huczyński
- Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Poznan, Poland
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25
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Balakrishna P, George S, Hatoum H, Mukherjee S. Serotonin Pathway in Cancer. Int J Mol Sci 2021; 22:1268. [PMID: 33525332 PMCID: PMC7865972 DOI: 10.3390/ijms22031268] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/12/2022] Open
Abstract
Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin's role as a neurotransmitter in the central nervous system and a motility mediator in the gastrointestinal tract has been well defined, and its function in tumorigenesis in various cancers (gliomas, carcinoids, and carcinomas) is being studied. Many studies have shown a potential stimulatory effect of serotonin on cancer cell proliferation, invasion, dissemination, and tumor angiogenesis. Although the underlying mechanism is complex, it is proposed that serotonin levels in the tumor and its interaction with specific receptor subtypes are associated with disease progression. This review article describes serotonin's role in cancer pathogenesis and the utility of the serotonin pathway as a potential therapeutic target in cancer treatment. Octreotide, an inhibitor of serotonin release, is used in well-differentiated neuroendocrine cancers, and the tryptophan hydroxylase (TPH) inhibitor, telotristat, is currently being investigated in clinical trials to treat patients with metastatic neuroendocrine tumors and advanced cholangiocarcinoma. Several in vitro studies have shown the anticancer effect of 5-HT receptor antagonists in various cancers such as prostate cancer, breast cancer, urinary bladder, colorectal cancer, carcinoid, and small-cell lung cancer. More in vivo studies are needed to assess serotonin's role in cancer and its potential use as an anticancer therapeutic target. Serotonin is also being evaluated for its immunoregulatory properties, and studies have shown its potential anti-inflammatory effect. Therefore, it would be of interest to explore the combination of serotonin antagonists with immunotherapy in the future.
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MESH Headings
- Antineoplastic Agents, Hormonal/therapeutic use
- Carcinoma, Neuroendocrine/blood supply
- Carcinoma, Neuroendocrine/drug therapy
- Carcinoma, Neuroendocrine/metabolism
- Carcinoma, Neuroendocrine/pathology
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Cholangiocarcinoma/blood supply
- Cholangiocarcinoma/drug therapy
- Cholangiocarcinoma/metabolism
- Cholangiocarcinoma/pathology
- Gene Expression Regulation, Neoplastic
- Humans
- Molecular Targeted Therapy/methods
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Octreotide/therapeutic use
- Phenylalanine/analogs & derivatives
- Phenylalanine/therapeutic use
- Pyrimidines/therapeutic use
- Receptors, Serotonin/genetics
- Receptors, Serotonin/metabolism
- Serotonin/metabolism
- Serotonin Antagonists/therapeutic use
- Signal Transduction/drug effects
- Signal Transduction/genetics
- Tryptophan Hydroxylase/genetics
- Tryptophan Hydroxylase/metabolism
- Tumor Cells, Cultured
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Affiliation(s)
- Pragathi Balakrishna
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (P.B.); (S.G.)
| | - Sagila George
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (P.B.); (S.G.)
| | - Hassan Hatoum
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (P.B.); (S.G.)
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Liang X, Hendryx M, Qi L, Lane D, Luo J. Association between prediagnosis depression and mortality among postmenopausal women with colorectal cancer. PLoS One 2021; 15:e0244728. [PMID: 33382778 PMCID: PMC7774930 DOI: 10.1371/journal.pone.0244728] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 12/15/2020] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND There are no epidemiologic data on the relation of depression before colorectal cancer diagnosis to colorectal cancer mortality among women with colorectal cancer, especially those who are postmenopausal. Our aim was to fill this research gap. METHODS We analyzed data from a large prospective cohort in the US, the Women's Health Initiative (WHI). The study included 2,396 women with incident colorectal cancer, assessed for depressive symptoms and antidepressant use before cancer diagnosis at baseline (screening visit in the WHI study) during 1993-1998. Participants were followed up from cancer diagnosis till 2018. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) between depression (depressive symptoms or antidepressant use) at baseline, and all-cause mortality and colorectal cancer-specific mortality. RESULTS Among women with colorectal cancer, there was no association between baseline depression and all-cause mortality or colorectal cancer-specific mortality after adjusting for age or multiple covariates. CONCLUSION Among women with colorectal cancer, there was no statistically significant association between depression before colorectal cancer diagnosis and all-cause mortality or colorectal cancer-specific mortality. Further studies are warranted to assess depressive symptoms and antidepressant use, measured at multiple points from baseline to diagnosis, and their interactions with specific types of colorectal cancer treatment on the risk of death from colorectal cancer.
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Affiliation(s)
- Xiaoyun Liang
- School of Social Development and Public Policy, Beijing Normal University, Beijing, China
| | - Michael Hendryx
- Department of Environmental and Occupational Health, School of Public Health, Indiana University Bloomington, Bloomington, Indiana, United States of America
| | - Lihong Qi
- Department of Public Health Sciences, University of California Davis, Davis, CA, United States of America
| | - Dorothy Lane
- Department of Family, Population and Preventive Medicine, Stony Brook University, School of Medicine, Stony Brook, New York, United States of America
| | - Juhua Luo
- Dept. of Epidemiology and Biostatistics, School of Public Health, Indiana University Bloomington, Bloomington, Indiana, United States of America
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27
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Crudden C, Shibano T, Song D, Dragomir MP, Cismas S, Serly J, Nedelcu D, Fuentes-Mattei E, Tica A, Calin GA, Girnita A, Girnita L. Inhibition of G Protein-Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth. Cancer Res 2020; 81:501-514. [PMID: 33158816 DOI: 10.1158/0008-5472.can-20-1662] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 10/03/2020] [Accepted: 10/30/2020] [Indexed: 11/16/2022]
Abstract
The ability of a receptor to preferentially activate only a subset of available downstream signal cascades is termed biased signaling. Although comprehensively recognized for the G protein-coupled receptors (GPCR), this process is scarcely explored downstream of receptor tyrosine kinases (RTK), including the cancer-relevant insulin-like growth factor-1 receptor (IGF1R). Successful IGF1R targeting requires receptor downregulation, yet therapy-mediated removal from the cell surface activates cancer-protective β-arrestin-biased signaling (β-arr-BS). As these overlapping processes are initiated by the β-arr/IGF1R interaction and controlled by GPCR-kinases (GRK), we explored GRKs as potential anticancer therapeutic targets to disconnect IGF1R downregulation and β-arr-BS. Transgenic modulation demonstrated that GRK2 inhibition or GRK6 overexpression enhanced degradation of IGF1R, but both scenarios sustained IGF1-induced β-arr-BS. Pharmacologic inhibition of GRK2 by the clinically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated the effects of GRK2 silencing with dose- and time-dependent IGF1R downregulation without associated β-arr-BS. In vivo, PX treatment caused substantial downregulation of IGF1R, suppressing the growth of Ewing's sarcoma xenografts. Functional studies reveal that PX exploits the antagonism between β-arrestin isoforms; in low ligand conditions, PX favored β-arrestin1/Mdm2-mediated ubiquitination/degradation of IGF1R, a scenario usually exclusive to ligand abundancy, making PX more effective than antibody-mediated IGF1R downregulation. This study provides the rationale, molecular mechanism, and validation of a clinically feasible concept for "system bias" targeting of the IGF1R to uncouple downregulation from signaling. Demonstrating system bias as an effective anticancer approach, our study reveals a novel strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF1R or other RTK. SIGNIFICANCE: This work provides insight into the molecular and biological roles of biased signaling downstream RTK and provides a novel "system bias" strategy to increase the efficacy of anti-IGF1R-targeted therapy in cancer.
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Affiliation(s)
- Caitrin Crudden
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.,Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Takashi Shibano
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Dawei Song
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Mihnea P Dragomir
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Sonia Cismas
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Julianna Serly
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Daniela Nedelcu
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Enrique Fuentes-Mattei
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Andrei Tica
- Department of Pharmacology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Ada Girnita
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.,Dermatology Department, Karolinska University Hospital, Stockholm, Sweden
| | - Leonard Girnita
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
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28
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Lee MJ, Huang CW, Chen YL, Yang YH, Chen VCH. Association between selective serotonin reuptake inhibitors and kidney cancer risk: A nationwide population-based cohort study. Int J Cancer 2020; 148:1331-1337. [PMID: 32965039 DOI: 10.1002/ijc.33307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/30/2020] [Accepted: 08/31/2020] [Indexed: 01/20/2023]
Abstract
The association between selective serotonin reuptake inhibitor (SSRI) exposure and cancer incidence has been investigated; however, no epidemiological study has investigated the association between exposure to individual SSRIs and kidney cancer incidence. The aim of this study is to examine whether SSRI use affected the risk of kidney cancer. We conducted a population-based retrospective cohort study using data from Taiwan's National Health Insurance Research Database. After adjusting for sex, age, urbanization level, comorbidity and medication use through propensity score matching, we identified 222 024 SSRI users and 221 361 SSRI nonusers. A robust Cox proportional hazards model was used to examine the associations between use of individual SSRIs and the risk of kidney cancer with 1- and 2-year induction periods. The result showed that SSRI users tended to be associated with a lower risk of kidney cancer with a 2-year induction period than nonusers; however, the association was not statistically significant (adjusted hazards ratio [aHR] = 0.88, 95% confidence interval [CI] = 0.77-1.01). We further examined the effects of individual SSRIs and observed a significantly lower risk of kidney cancer associated with the use of citalopram (aHR = 0.67, 95% CI = 0.47-0.96) and paroxetine (aHR = 0.75, 95% CI = 0.58-0.97) with the 2-year induction period. These findings support that SSRIs are associated with decreased kidney cancer risk and indicate that citalopram and paroxetine have protective effects in depressed patients with kidney cancer.
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Affiliation(s)
- Min-Jing Lee
- Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chien-Wei Huang
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, Taiwan.,School of Medicine, National Yang-Ming University, Taiwan
| | - Yi-Lung Chen
- Department of Healthcare Administration, Asia University, Taichung, Taiwan.,Department of Psychology, Asia University, Taichung, Taiwan
| | - Yao-Hsu Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.,Health Information and Epidemiology Laboratory, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Vincent Chin-Hung Chen
- Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan
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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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The Impact of Beta Blockers on Survival Outcomes in Patients With Non-small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors. Clin Lung Cancer 2020; 22:e57-e62. [PMID: 32900613 DOI: 10.1016/j.cllc.2020.07.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 07/20/2020] [Accepted: 07/27/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Beta blockers have been associated with anti-tumorigenic effects, potentially by reducing adrenergic-mediated stress responses. Preclinical studies have additionally shown that beta blockade may enhance the efficacy of cancer immunotherapy. We investigated patients with lung cancer who concomitantly used beta blockers and immune checkpoint inhibitors (ICIs), with the hypothesis that beta blockade would positively impact clinical outcomes. PATIENTS AND METHODS We retrospectively reviewed the health records of 109 patients who were treated at Northwestern University from January 2014 through August 2018 with ICIs for non-small-cell lung cancer (NSCLC). Comparisons of overall survival and progression-free survival (PFS) were performed using Kaplan-Meier analysis with log-rank test, and a univariate regression analysis was performed with a Cox proportional hazards model. RESULTS Among 109 patients treated with ICIs for NSCLC, 28 of them were concomitantly prescribed beta blockers. Use of beta blockers was associated with increased PFS, with a hazard ratio of 0.58 and 95% confidence interval of 0.36 to 0.93. There was not a significant increase in overall survival among patients who took beta blockers (hazard ratio, 0.66; 95% confidence interval, 0.38-1.17). In a regression model, beta blockers were identified as predictive of PFS, as were non-squamous histology, tumor programmed death-ligand 1 positivity, and lower line of treatment. CONCLUSIONS Our data suggests beta blocker use may be associated with improved PFS among patients treated with ICIs for NSCLC. This was a small study, and these findings should be further validated in prospective clinical studies.
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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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Liu YC, Chen VCH, Lu ML, Lee MJ, McIntyre RS, Majeed A, Lee Y, Chen YL. The Association between Selective Serotonin Reuptake Inhibitors (SSRIs) Use and the Risk of Bladder Cancer: A Nationwide Population-Based Cohort Study. Cancers (Basel) 2020; 12:cancers12051184. [PMID: 32392848 PMCID: PMC7281365 DOI: 10.3390/cancers12051184] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 04/30/2020] [Accepted: 05/04/2020] [Indexed: 02/01/2023] Open
Abstract
Background: Past studies suggest mixed associations between selective serotonin reuptake inhibitor (SSRI) prescription and carcinogenic risk. There is no epidemiological study reporting on the association between SSRI use and the incidence of bladder cancer. The aim of this study is to determine whether SSRI use influences the risk of bladder cancer. Methods: We conducted a nationwide retrospective cohort study by Taiwan’s National Health Insurance Research Database from January 1, 1997 to December 31, 2013. 192,392 SSRI prescribed individuals were randomly matched 1 to 1 with 191,786 individuals who had never received any SSRIs by propensity scores match. The Cox Proportional Hazard models were conducted to examine the risk of bladder cancer between individuals prescribed SSRIs and individuals not prescribed SSRIs. Results: SSRIs were associated with significant reduced risk of bladder cancer with 0.5, 1, and 2 year induction periods (adjusted hazard ratio (aHR) = 0.86, 95% CI (confidence interval) = 0.76–0.98, aHR = 0.85, 95% CI = 0.75–0.97, and aHR = 0.77, 95% CI = 0.66–0.89). When examining the effect of specific SSRI, there was significantly lower risk of bladder cancer in individuals prescribed fluoxetine (6 month induction period: aHR = 0.78, 95% CI = 0.65–0.93; 1 year induction period: aHR = 0.78, 95% CI = 0.65–0.94; 2 year induction period: aHR = 0.73, 95% CI = 0.60–0.89), paroxetine (6 month induction period: aHR = 0.78, 95% CI = 0.61–0.99; 1 year induction period: aHR = 0.79, 95% CI = 0.61–1.01; 2 year induction period: aHR = 0.72, 95% CI = 0.54–0.95), and citalopram (6 month induction period: aHR = 0.74, 95% CI = 0.53–1.03; 1 year induction period: aHR = 0.70, 95% CI = 0.50–0.99; 2 year induction period: aHR = 0.60, 95% CI = 0.41–0.88). Conclusions: Individuals prescribed fluoxetine, paroxetine, or citalopram had a reduced risk of bladder cancer in this large, cross-national database.
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Affiliation(s)
- Yi-Chun Liu
- Taichung Hospital, Ministry of Health and Welfare, Taichung 40343, Taiwan;
| | - Vincent Chin-Hung Chen
- School of Medicine, Chang Gung University, Tauyuan 33302, Taiwan; (V.C.-H.C.); (M.-J.L.)
- Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Mong-Liang Lu
- Department of Psychiatry, Wan Fang Hospital and School of Medicine, College of Medicine, Taipei Medical University, Taipei 11696, Taiwan;
| | - Min-Jing Lee
- School of Medicine, Chang Gung University, Tauyuan 33302, Taiwan; (V.C.-H.C.); (M.-J.L.)
- Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Roger S. McIntyre
- Department of Psychiatry, University of Toronto, Toronto 399, ON M5T 2S8, Canada;
| | - Amna Majeed
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto 399, ON M5T 2S8, Canada; (A.M.); (Y.L.)
| | - Yena Lee
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto 399, ON M5T 2S8, Canada; (A.M.); (Y.L.)
| | - Yi-Lung Chen
- Department of Healthcare Administration, Asia University, Taichung 41354, Taiwan
- Department of Psychology, Asia University, Taichung 41354, Taiwan
- Correspondence: ; Tel.: +886-4-23323456 (ext. 20106); Fax: +886-4-23321206
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Abstract
Being originally discovered as cellular recycling bins, lysosomes are today recognized as versatile signaling organelles that control a wide range of cellular functions that are essential not only for the well-being of normal cells but also for malignant transformation and cancer progression. In addition to their core functions in waste disposal and recycling of macromolecules and energy, lysosomes serve as an indispensable support system for malignant phenotype by promoting cell growth, cytoprotective autophagy, drug resistance, pH homeostasis, invasion, metastasis, and genomic integrity. On the other hand, malignant transformation reduces the stability of lysosomal membranes rendering cancer cells sensitive to lysosome-dependent cell death. Notably, many clinically approved cationic amphiphilic drugs widely used for the treatment of other diseases accumulate in lysosomes, interfere with their cancer-promoting and cancer-supporting functions and destabilize their membranes thereby opening intriguing possibilities for cancer therapy. Here, we review the emerging evidence that supports the supplementation of current cancer therapies with lysosome-targeting cationic amphiphilic drugs.
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Tuszynski J, Tilli TM, Levin M. Ion Channel and Neurotransmitter Modulators as Electroceutical Approaches to the Control of Cancer. Curr Pharm Des 2019; 23:4827-4841. [PMID: 28554310 PMCID: PMC6340161 DOI: 10.2174/1381612823666170530105837] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 05/17/2017] [Accepted: 05/23/2017] [Indexed: 11/22/2022]
Abstract
The activities of individual cells must be tightly coordinated in order to build and maintain complex 3-dimensional body structures during embryogenesis and regeneration. Thus, one way to view cancer is within systems biology as a network disorder affecting the ability of cells to properly interact with a morphodynamic field of instructive signals that keeps proliferation and migration orchestrated toward the anatomical needs of the host or-ganism. One layer of this set of instructive microenvironmental cues is bioelectrical. Voltage gradients among all somatic cells (not just excitable nerve and muscle) control cell behavior, and the ionic coupling of cells into networks via electrochemical synapses allows them to implement tissue-level patterning decisions. These gradients have been increasingly impli-cated in the induction and suppression of tumorigenesis and metastasis, in the emerging links between developmental bioelectricity to the cancer problem. Consistent with the well-known role of neurotransmitter molecules in transducing electrical activity to downstream cascades in the brain, serotonergic signaling has likewise been implicated in cancer. Here, we review these recent data and propose new approaches for manipulating bioelectric and neurotransmitter pathways in cancer biology based on a bioelectric view of cancer. To sup-port this methodology, we present new data on the effects of the SSRI Prozac and its analog (ZINC ID = ZINC06811610) on survival of both cancer (MCF7) and normal (MCF10A) breast cells exposed to these compounds. We found an IC50 concentration (25 μM for Pro-zac and 100 μM for the Prozac analog) at which these compounds inhibited tumor cell sur-vival and proliferation. Additionally, at these concentrations, we did not observe alterations in a non-tumoral cell line. This constitutes a proof-of-concept demonstration for our hy-pothesis that the use of both existing and novel drugs as electroceuticals could serve as an alternative to highly toxic chemotherapy strategies replacing or augmenting them with less toxic alternatives. We believe this new approach forms an exciting roadmap for future bio-medical advances.
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Affiliation(s)
- Jack Tuszynski
- Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta. Canada
| | - Tatiana M Tilli
- Laboratory of Biological System Modeling, National Institute for Science and Technology on Innovation in Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro. Brazil
| | - Michael Levin
- Biology Department, and Allen Discovery Center, Tufts University, Medford, MA, 02155. United States
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Xu J, Li Y, Lv Y, Bian C, You X, Endoh D, Teraoka H, Shi Q. Molecular Evolution of Tryptophan Hydroxylases in Vertebrates: A Comparative Genomic Survey. Genes (Basel) 2019; 10:E203. [PMID: 30857219 PMCID: PMC6470480 DOI: 10.3390/genes10030203] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 02/19/2019] [Accepted: 03/04/2019] [Indexed: 02/02/2023] Open
Abstract
Serotonin is a neurotransmitter involved in various physiological processes in the central and peripheral nervous systems. Serotonin is also a precursor for melatonin biosynthesis, which mainly occurs in the pineal gland of vertebrates. Tryptophan hydroxylase (TPH) acts as the rate-limiting enzyme in serotonin biosynthesis and is the initial enzyme involved in the synthesis of melatonin. Recently, two enzymes-TPH1 and TPH2-were reported to form the TPH family in vertebrates and to play divergent roles in serotonergic systems. Here, we examined the evolution of the TPH family from 70 vertebrate genomes. Based on the sequence similarity, we extracted 184 predicted tph homologs in the examined vertebrates. A phylogenetic tree, constructed on the basis of these protein sequences, indicated that tph genes could be divided into two main clades (tph1 and tph2), and that the two clades were further split into two subgroups of tetrapods and Actinopterygii. In tetrapods, and some basal non-teleost ray-finned fishes, only two tph isotypes exist. Notably, tph1 in most teleosts that had undergone the teleost-specific genome duplication could be further divided into tph1a and tph1b. Moreover, protein sequence comparisons indicated that TPH protein changes among vertebrates were concentrated at the NH₂-terminal. The tertiary structures of TPH1 and TPH2 revealed obvious differences in the structural elements. Five positively selected sites were characterized in TPH2 compared with TPH1; these sites may reflect the functional divergence in enzyme activity and substrate specificity. In summary, our current work provides novel insights into the evolution of tph genes in vertebrates from a comprehensive genomic perspective.
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Affiliation(s)
- Junmin Xu
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Japan.
| | - Yanping Li
- BGI-Shenzhen, Shenzhen 518083, China.
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China.
| | - Yunyun Lv
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China.
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China.
| | - Chao Bian
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China.
| | - Xinxin You
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China.
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China.
| | - Daiji Endoh
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Japan.
| | - Hiroki Teraoka
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Japan.
| | - Qiong Shi
- BGI-Shenzhen, Shenzhen 518083, China.
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China.
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China.
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Madhusoodanan S, Ting MB, Wilson SY. The psychopharmacology of primary and metastatic brain tumors and paraneoplastic syndromes. HANDBOOK OF CLINICAL NEUROLOGY 2019; 165:269-283. [PMID: 31727217 DOI: 10.1016/b978-0-444-64012-3.00016-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Brain tumors and paraneoplastic syndromes can cause various neuropsychiatric symptoms. Rarely, psychiatric symptoms may be the initial presentation of the underlying neurologic lesion. Brain imaging studies are crucial in the diagnosis of brain tumors. Paraneoplastic syndromes are mostly immune-mediated, and antineuronal antibodies may be detected in the blood or cerebrospinal fluid. Clinical suspicion is very important in assisting the diagnostic workup. Treatment of the psychiatric symptoms depends on the nature of the symptoms. Selection of the psychotropic agent has to be done carefully to minimize complications such as seizures and delirium secondary to anticholinergic toxicity. With advances in targeted therapies, immunology, and genetics, the future appears more promising.
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Affiliation(s)
- Subramoniam Madhusoodanan
- Department of Psychiatry, St. John's Episcopal Hospital, New York, NY, United States; Department of Psychiatry, SUNY Health Science Center at Brooklyn, New York, NY, United States.
| | - Mark Bryan Ting
- Community Behavioral Health Center, Fresno, CA, United States
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Jang WJ, Jung SK, Vo TTL, Jeong CH. Anticancer activity of paroxetine in human colon cancer cells: Involvement of MET and ERBB3. J Cell Mol Med 2018; 23:1106-1115. [PMID: 30421568 PMCID: PMC6349215 DOI: 10.1111/jcmm.14011] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 07/18/2018] [Accepted: 08/16/2018] [Indexed: 12/28/2022] Open
Abstract
The concept of drug repositioning has recently received considerable attention in the field of oncology. In the present study, we propose that paroxetine can be used as a potent anticancer drug. Paroxetine, one of the selective serotonin reuptake inhibitors (SSRIs), has been widely prescribed for the treatment of depression and anxiety disorders. Recently, SSRIs have been reported to have anticancer activity in various types of cancer cells; however, the underlying mechanisms of their action are not yet known. In this study, we investigated the potential anticancer effect of paroxetine in human colorectal cancer cells, HCT116 and HT‐29. Treatment with paroxetine reduced cell viability, which was associated with marked increase in apoptosis, in both the cell lines. Also, paroxetine effectively inhibited colony formation and 3D spheroid formation. We speculated that the mode of action of paroxetine might be through the inhibition of two major receptor tyrosine kinases – MET and ERBB3 – leading to the suppression of AKT, ERK and p38 activation and induction of JNK and caspase‐3 pathways. Moreover, in vivo experiments revealed that treatment of athymic nude mice bearing HT‐29 cells with paroxetine remarkably suppressed tumour growth. In conclusion, paroxetine is a potential therapeutic option for patients with colorectal cancer.
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Affiliation(s)
- Won-Jun Jang
- College of Pharmacy, Keimyung University, Daegu, Korea
| | - Sung Keun Jung
- School of Food Science and Biotechnology, Kyungpook National University, Daegu, Korea
| | | | - Chul-Ho Jeong
- College of Pharmacy, Keimyung University, Daegu, Korea
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D’Arcy M, Stürmer T, Lund JL. The importance and implications of comparator selection in pharmacoepidemiologic research. CURR EPIDEMIOL REP 2018; 5:272-283. [PMID: 30666285 PMCID: PMC6338470 DOI: 10.1007/s40471-018-0155-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW Pharmacoepidemiologic studies employing large databases are critical to evaluating the effectiveness and safety of drug exposures in large and diverse populations. Because treatment is not randomized, researchers must select a relevant comparison group for the treatment of interest. The comparator group can consist of individuals initiating: (1) a similarly indicated treatment (active comparator), (2) a treatment used for a different indication (inactive comparator) or (3) no particular treatment (non-initiators). Herein we review recent literature and describe considerations and implications of comparator selection in pharmacoepidemiologic studies. RECENT FINDINGS Comparator selection depends on the scientific question and feasibility constraints. Because pharmacoepidemiologic studies rely on the choice to initiate or not initiate a specific treatment, rather than randomization, they are at-risk for confounding related to the comparator choice including: by indication, disease severity and frailty. We describe forms of confounding specific to pharmacoepidemiologic studies and discuss each comparator along with informative examples and a case study. We provide commentary on potential issues relevant to comparator selection in each study, highlighting the importance of understanding the population in whom the treatment is given and how patient characteristics are associated with the outcome. SUMMARY Advanced statistical techniques may be insufficient for reducing confounding in observational studies. Evaluating the extent to which comparator selection may mitigate or induce systematic bias is a critical component of pharmacoepidemiologic studies.
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Affiliation(s)
- Monica D’Arcy
- Department of Epidemiology, Gillings School of Global
Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Til Stürmer
- Department of Epidemiology, Gillings School of Global
Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Jennifer L. Lund
- Department of Epidemiology, Gillings School of Global
Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Gao H, Zhang IY, Zhang L, Song Y, Liu S, Ren H, Liu H, Zhou H, Su Y, Yang Y, Badie B. S100B suppression alters polarization of infiltrating myeloid-derived cells in gliomas and inhibits tumor growth. Cancer Lett 2018; 439:91-100. [PMID: 30076898 PMCID: PMC7048242 DOI: 10.1016/j.canlet.2018.07.034] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 07/24/2018] [Accepted: 07/25/2018] [Indexed: 01/03/2023]
Abstract
S100B, a member of the multigene family of Ca2+-binding proteins, is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of STAT3. Furthermore, S100B downregulation in a murine glioma model inhibited macrophage trafficking and tumor growth. Based on these observations, we hypothesized that S100B inhibitors may have antiglioma properties through modulation of tumor microenvironment. To discover novel S100B inhibitors, we developed a high-throughput screening cell-based S100B promoter-driven luciferase reporter assay. Initial screening of 768 compounds in the NIH library identified 36 hits with >85% S100B inhibitory activity. Duloxetine (Dul, an SNRI) was selected for the initial proof-of-concept studies. At low concentrations (1–5 μM) Dul inhibited S100B and CCL2 production in mouse GL261 glioma cells, but had minimal cytotoxic activity in vitro. In vivo, however, Dul (30 mg/kg/14 days) inhibited S100B production, altered the polarization and trafficking of tumor-associated myeloid-derived cells, and inhibited the growth of intracranial GL261 gliomas. Dul therapeutic efficacy, however, was not observed in the K-Luc glioma model that expresses low levels of S100B. These findings affirm the role of S100B in gliomagenesis and justify the development of more potent S100B inhibitors for glioma therapy.
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Affiliation(s)
- Hang Gao
- Department of Bone and Joint Surgery, No.1 Hospital of Jilin University, Changchun, Jilin Province, PR China.
| | - Ian Y Zhang
- Division of Neurosurgery, City of Hope Beckman Research Institute, USA.
| | - Leying Zhang
- Division of Neurosurgery, City of Hope Beckman Research Institute, USA.
| | - Yanyan Song
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, Jilin Province, PR China.
| | - Shunan Liu
- Department of Pharmacology, The Pharmacy School of Jilin University, Changchun, Jilin Province, PR China.
| | - Hui Ren
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, PR China.
| | - Huili Liu
- Division of Neurosurgery, City of Hope Beckman Research Institute, USA.
| | - Hui Zhou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, PR China.
| | - Yanping Su
- College of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, PR China.
| | - Yihang Yang
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, PR China.
| | - Behnam Badie
- Department of Cancer Immunotherapeutics & Tumor Immunology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA.
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Ballou Y, Rivas A, Belmont A, Patel L, Amaya CN, Lipson S, Khayou T, Dickerson EB, Nahleh Z, Bryan BA. 5-HT serotonin receptors modulate mitogenic signaling and impact tumor cell viability. Mol Clin Oncol 2018; 9:243-254. [PMID: 30155245 PMCID: PMC6109681 DOI: 10.3892/mco.2018.1681] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 07/13/2018] [Indexed: 02/06/2023] Open
Abstract
Symptoms of depression are present in over half of all cancer patients, and selective serotonin reuptake inhibitor (SSRI) anti-depressant medications are prescribed to nearly a quarter of these individuals in order to cope with their disease. Previous studies have provided evidence that elevated serotonin (5-HT) and serotonin receptor levels may contribute to oncogenic progression, yet little is known regarding the mechanism by which this occurs. The data demonstrated that serotonin receptor mRNAs and proteins are expressed across diverse cancer types, and that serotonin stimulation of tumor cells activates oncogenic signaling mediators including components of the AKT, CREB, GSK3, and MAPK pathways. Selective pharmacological inhibition of the seven known classes of 5-HT receptors in sarcoma and breast cancer cells resulted in dose dependent decreases in tumor cell viability, activation of the p53 DNA damage pathway, suppression of MAPK activity, and significantly reduced tumor volume in an in ovo model. Based on a retrospective clinical analysis of 419 patients diagnosed with breast cancer, we discovered that use of SSRIs was associated with a 2.3-fold increase in tumor proliferation rates for late stage patients based on their Ki-67 index (P=0.03). These data provide evidence that serotonin signaling pathways, which treating oncologists often pharmacologically target to assist cancer patients to psychologically cope with their illness, activate signaling pathways known to promote tumor growth and survival.
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Affiliation(s)
- Yessenia Ballou
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA
| | - Alexandria Rivas
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA
| | - Andres Belmont
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA
| | - Luv Patel
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA
| | - Clarissa N Amaya
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA
| | - Shane Lipson
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA
| | - Thuraieh Khayou
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA
| | - Erin B Dickerson
- Department of Veterinary Clinical Sciences, University of Minnesota, Saint Paul, MN 55108, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Zeina Nahleh
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.,Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.,Department of Hematology and Medical Oncology, Cleveland Clinic Florida, Weston, FL 33331, USA
| | - Brad A Bryan
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.,Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA
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Di Rosso ME, Sterle HA, Cremaschi GA, Genaro AM. Beneficial Effect of Fluoxetine and Sertraline on Chronic Stress-Induced Tumor Growth and Cell Dissemination in a Mouse Model of Lymphoma: Crucial Role of Antitumor Immunity. Front Immunol 2018; 9:1341. [PMID: 29971064 PMCID: PMC6018164 DOI: 10.3389/fimmu.2018.01341] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 05/29/2018] [Indexed: 01/06/2023] Open
Abstract
Clinical data and experimental studies have suggested a relationship between psychosocial factors and cancer prognosis. Both, stress effects on the immune system and on tumor biology were analyzed independently. However, there are few studies regarding the stress influence on the interplay between the immune system and tumor biology. Moreover, antidepressants have been used in patients with cancer to alleviate mood disorders. Nevertheless, there is contradictory evidence about their action on cancer prognosis. In this context, we investigated the effect of chronic stress on tumor progression taking into account both its influence on the immune system and on tumor biology. Furthermore, we analyzed the action of selective serotonin reuptake inhibitors, fluoxetine and sertraline, in these effects. For this purpose, C57BL/6J mice submitted or not to a chronic stress model and treated or not with fluoxetine or sertraline were subcutaneously inoculated with EL4 cells to develop solid tumors. Our results indicated that chronic stress leads to an increase in both tumor growth and tumor cell dissemination. The analysis of cell cycle regulatory proteins showed that stress induced an increase in the mRNA levels of cyclins A2, D1, and D3 and a decrease in mRNA levels of cell cycle inhibitors p15, p16, p21, p27, stimulating cell cycle progression. Moreover, an augment of mRNA levels of metalloproteases (MMP-2 and MMP-9), a decrease of inhibitors of metalloproteases mRNA levels (TIMP 1, 2, and 3), and an increase in migration ability were found in tumors from stressed animals. In addition, a significant decrease of antitumor immune response in animals under stress was found. Adoptive lymphoid cell transfer experiments indicated that the reduced immune response in stressed animals influenced both the tumor growth and the metastatic capacity of tumor cells. Finally, we found an important beneficious effect of fluoxetine or sertraline treatment on cancer progression. Our results emphasize the crucial role of the immune system in tumor progression under stress situations. Although a direct effect of stress and drug treatment on tumor biology could not be ruled out, the beneficial effect of fluoxetine and sertraline appears to be mainly due to a restoration of antitumor immune response.
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Affiliation(s)
- María Emilia Di Rosso
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Católica Argentina (UCA), Ciudad de Buenos Aires, Argentina
| | - Helena Andrea Sterle
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Católica Argentina (UCA), Ciudad de Buenos Aires, Argentina
| | - Graciela Alicia Cremaschi
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Católica Argentina (UCA), Ciudad de Buenos Aires, Argentina
| | - Ana María Genaro
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Católica Argentina (UCA), Ciudad de Buenos Aires, Argentina.,Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires (UBA), Ciudad de Buenos Aires, Argentina
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42
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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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Sakka L, Delétage N, Chalus M, Aissouni Y, Sylvain-Vidal V, Gobron S, Coll G. Assessment of citalopram and escitalopram on neuroblastoma cell lines. Cell toxicity and gene modulation. Oncotarget 2018; 8:42789-42807. [PMID: 28467792 PMCID: PMC5522106 DOI: 10.18632/oncotarget.17050] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 03/15/2017] [Indexed: 12/13/2022] Open
Abstract
Selective serotonin reuptake inhibitors (SSRI) are common antidepressants which cytotoxicity has been assessed in cancers notably colorectal carcinomas and glioma cell lines. We assessed and compared the cytotoxicity of 2 SSRI, citalopram and escitalopram, on neuroblastoma cell lines. The study was performed on 2 non-MYCN amplified cell lines (rat B104 and human SH-SY5Y) and 2 human MYCN amplified cell lines (IMR32 and Kelly). Citalopram and escitalopram showed concentration-dependent cytotoxicity on all cell lines. Citalopram was more cytotoxic than escitalopram. IMR32 was the most sensitive cell line. The absence of toxicity on human primary Schwann cells demonstrated the safety of both molecules for myelin. The mechanisms of cytotoxicity were explored using gene-expression profiles and quantitative real-time PCR (qPCR). Citalopram modulated 1 502 genes and escitalopram 1 164 genes with a fold change ≥ 2. 1 021 genes were modulated by both citalopram and escitalopram; 481 genes were regulated only by citalopram while 143 genes were regulated only by escitalopram. Citalopram modulated 69 pathways (KEGG) and escitalopram 42. Ten pathways were differently modulated by citalopram and escitalopram. Citalopram drastically decreased the expression of MYBL2, BIRC5 and BARD1 poor prognosis factors of neuroblastoma with fold-changes of -107 (p<2.26 10−7), -24.1 (p<5.6 10−9) and -17.7 (p<1.2 10−7). CCNE1, AURKA, IGF2, MYCN and ERBB2 were more moderately down-regulated by both molecules. Glioma markers E2F1, DAPK1 and CCND1 were down-regulated. Citalopram displayed more powerful action with broader and distinct spectrum of action than escitalopram.
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Affiliation(s)
- Laurent Sakka
- Laboratoire d'Anatomie et d'Organogenèse, Laboratoire de Biophysique Sensorielle, NeuroDol, Faculté de Médecine, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.,Service de Neurochirurgie, Pole RMND, CHU de Clermont-Ferrand, Hôpital Gabriel-Montpied, 63003 Clermont-Ferrand Cedex, France
| | - Nathalie Delétage
- Neuronax SAS, Biopôle Clermont-Limagne, F-63360 Saint-Beauzire, France
| | - Maryse Chalus
- Laboratoire d'Anatomie et d'Organogenèse, Laboratoire de Biophysique Sensorielle, NeuroDol, Faculté de Médecine, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France
| | - Youssef Aissouni
- Laboratoire de Pharmacologie Fondamentale et Clinique de la Douleur, NeuroDol, Faculté de Médecine, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France
| | | | - Stéphane Gobron
- Neuronax SAS, Biopôle Clermont-Limagne, F-63360 Saint-Beauzire, France
| | - Guillaume Coll
- Service de Neurochirurgie, Pole RMND, CHU de Clermont-Ferrand, Hôpital Gabriel-Montpied, 63003 Clermont-Ferrand Cedex, France
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Hepatocellular carcinoma and antidepressants: a nationwide population-based study. Oncotarget 2018; 8:30464-30470. [PMID: 27783998 PMCID: PMC5444756 DOI: 10.18632/oncotarget.12826] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 10/19/2016] [Indexed: 11/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is highly prevalent in Asia. Antidepressants have been associated with increase in hepatocellular carcinoma. This is the first Asian population-based study to evaluate the association between antidepressant use and risk of HCC. Based on Taiwan's National Health Insurance Research Database, we conducted a nationwide population-based study. A total of 49,998 cases with HCC were identified and paired with 244,236 randomly selected controls. The data was analyzed via the conditional logistic regression model adjusting for several confounding factors. Use of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) was associated with lower risk for HCC. No apparent association was found between use of other classes of antidepressants and HCC, including monoamine oxidase inhibitors (MAOIs), serotonin norepinephrine reuptake inhibitors (SNRIs), trazodone, mirtazapine and bupropion. The findings of a protective effect of TCAs and SSRIs for HCC should be interpreted with caution and warrants further research.
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45
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Pan J, Xu Y, Song H, Zhou X, Yao Z, Ji G. Extracts of Zuo Jin Wan, a traditional Chinese medicine, phenocopies 5-HTR1D antagonist in attenuating Wnt/β-catenin signaling in colorectal cancer cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:506. [PMID: 29183322 PMCID: PMC5706385 DOI: 10.1186/s12906-017-2006-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 11/14/2017] [Indexed: 01/30/2023]
Abstract
BACKGROUND In vitro and in vivo studies have shown that Zuo Jin Wan (ZJW), a herbal formula of traditional Chinese medicine (TCM), possessed anticancer properties. However, the underlying mechanism for the action of ZJW remains unclear. Various subtypes of 5-Hydroxytryptamine receptor (5-HTR) have been shown to play a role in carcinogenesis and cancer metastasis. 5-HTR1D, among the subtypes, is highly expressed in colorectal cancer (CRC) cell lines and tissues. The present study aimed at investigating effect of ZJW extracts on the biological function of CRC cells, the expression of 5-HTR1D, and molecules of Wnt/β-catenin signaling pathway. METHODS In this study, the effect of ZJW extracts on 5-HTR1D expression and Wnt/β-catenin signaling pathway were investigated and contrasted with GR127935 (GR), a known 5-HTR1D antagonist, using the CRC cell line SW403. The cells were respectively treated with GR127935 and different doses of ZJW extracts. Proliferation, apoptosis, migration, and invasion of SW403 cells were compared between ZJW and GR127935 treatments. The expression of 5-HTR1D and signaling molecules involved in the canonic Wnt/β-catenin pathway were determined by Western blot analysis. RESULTS After ZJW extracts treatment and GR127935 treatment, G1 arrest in cell cycle of SW403 was increased. Cell apoptosis was pronounced, and cell migration and invasion were suppressed. SW403 cells showed a dose-dependently decreased expression of 5-HTR1D, meanwhile, β-catenin level was significantly decreased in nucleus of cells cultured with GR127935. Treatment of ZJW extracts dose-dependently resulted in decreased 5-HTR1D and a concomitant reduction in the Wnt/β-catenin signal transduction, an effect indistinguishable from GR127935 treatment. CONCLUSION The anticancer activity of ZJW extracts may be partially achieved through attenuation of the 5-HTR1D-Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Jielu Pan
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Yangxian Xu
- Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Haiyan Song
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Xiqiu Zhou
- Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Zemin Yao
- Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5 Canada
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
- E-Institute of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China
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46
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Nayan M, Juurlink DN, Austin PC, Macdonald EM, Finelli A, Kulkarni GS, Hamilton RJ. Medication use and kidney cancer risk: A population-based study. Eur J Cancer 2017; 83:203-210. [DOI: 10.1016/j.ejca.2017.07.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 06/29/2017] [Accepted: 07/03/2017] [Indexed: 02/08/2023]
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The role of enteric neurons in the development and progression of colorectal cancer. Biochim Biophys Acta Rev Cancer 2017; 1868:420-434. [PMID: 28847715 DOI: 10.1016/j.bbcan.2017.08.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 08/16/2017] [Accepted: 08/17/2017] [Indexed: 02/06/2023]
Abstract
The enteric nervous system (ENS) is the intrinsic neural network of the gastrointestinal tract, which is essential for regulating gut functions and intestinal homeostasis. The importance of the ENS is underscored by the existence of severe gastrointestinal diseases, such as Hirschsprung's disease and intestinal pseudo-obstruction, which arise when the ENS fails to develop normally or becomes dysregulated. Moreover, it is known that enteric neurons are involved in intestinal inflammation. However, the role of the ENS in colorectal cancer (CRC) carcinogenesis remains poorly understood, even though processes like perineural invasion and neoneurogenesis are important factors in CRC. Here we summarize how enteric neurons are affected during CRC and discuss the influence of enteric neurons, either direct or indirect, on the development and/or progression of CRC. Finally, we illustrate how the ENS could be targeted as a potential anti-cancer therapy, establishing the ENS as an integral part of the tumor microenvironment.
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Chan HL, Chiu WC, Chen VCH, Huang KY, Wang TN, Lee Y, McIntyre RS, Hsu TC, Lee CTC, Tzang BS. SSRIs associated with decreased risk of hepatocellular carcinoma: A population-based case-control study. Psychooncology 2017; 27:187-192. [PMID: 28666060 DOI: 10.1002/pon.4493] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 05/18/2017] [Accepted: 06/27/2017] [Indexed: 12/26/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the second leading cancer-related cause of mortality worldwide. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are commonly used worldwide. Available evidence investigating the association between SSRIs use and HCC risk is limited. OBJECTIVE The present study aimed to investigate if the effect of all kinds of SSRIs on HCC was the same or not using population-based study. METHODS The nationwide population-based study herein using Taiwan's National Health Insurance Research Database included a total of 59 859 cases with HCC and 285 124 matched controls. Conditional logistic regression analyses were adjusted for confounding variables. RESULTS All common kinds of SSRIs including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine were associated with lower HCC risk, and the findings were dose-dependent (eg, fluoxetine: 1-28 DDD [defined daily dose]: adjusted odds ratio [aOR]: 0.81, 95% confidence interval [CI], 0.73-0.89; 29-365 DDD: aOR: 0.71, 95% CI, 0.64-0.79; and ≥366 DDD: aOR: 0.55, 95% CI, 0.45-0.67) (P for trend < .001). CONCLUSIONS All kinds of SSRIs were associated with decreased risk of HCC.
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Affiliation(s)
- Hsiang-Lin Chan
- Department of Psychiatry, Chang Gung University, Taoyuan, Taiwan.,Department of Child Psychiatry, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei-Che Chiu
- Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan.,School of Medicine, Fu Jen Catholic University, Taipei, Taiwan
| | - Vincent Chin-Hung Chen
- Department of Psychiatry, Chang Gung University, Taoyuan, Taiwan.,Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Kuo-You Huang
- Department of Speech, Language Pathology and Audiology, Chung Shan Medical University, Taichung, Taiwan
| | - Tsu-Nai Wang
- Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yena Lee
- Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, Canada
| | - Roger S McIntyre
- Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, Canada.,Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada
| | - Tsai-Ching Hsu
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.,Immunology Research Center, Chung Shan Medical University, Taichung, Taiwan, ROC.,Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Charles Tzu-Chi Lee
- Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan
| | - Bor-Show Tzang
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.,Immunology Research Center, Chung Shan Medical University, Taichung, Taiwan, ROC.,Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.,Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Boia-Ferreira M, Basílio AB, Hamasaki AE, Matsubara FH, Appel MH, Da Costa CRV, Amson R, Telerman A, Chaim OM, Veiga SS, Senff-Ribeiro A. TCTP as a therapeutic target in melanoma treatment. Br J Cancer 2017; 117:656-665. [PMID: 28751755 PMCID: PMC5572181 DOI: 10.1038/bjc.2017.230] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/27/2017] [Accepted: 06/23/2017] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Translationally controlled tumour protein (TCTP) is an antiapoptotic protein highly conserved through phylogeny. Translationally controlled tumour protein overexpression was detected in several tumour types. Silencing TCTP was shown to induce tumour reversion. There is a reciprocal repression between TCTP and P53. Sertraline interacts with TCTP and decreases its cellular levels. METHODS We evaluate the role of TCTP in melanoma using sertraline and siRNA. Cell viability, migration, and clonogenicity were assessed in human and murine melanoma cells in vitro. Sertraline was evaluated in a murine melanoma model and was compared with dacarbazine, a major chemotherapeutic agent used in melanoma treatment. RESULTS Inhibition of TCTP levels decreases melanoma cell viability, migration, clonogenicity, and in vivo tumour growth. Human melanoma cells treated with sertraline show diminished migration properties and capacity to form colonies. Sertraline was effective in inhibiting tumour growth in a murine melanoma model; its effect was stronger when compared with dacarbazine. CONCLUSIONS Altogether, these results indicate that sertraline could be effective against melanoma and TCTP can be a target for melanoma therapy.
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Affiliation(s)
- M Boia-Ferreira
- Department of Cell Biology, Centro Politécnico, Federal University of Paraná, UFPR, Jardim das Américas, CEP 81531-990, Curitiba, Paraná, Brazil
| | - A B Basílio
- Department of Cell Biology, Centro Politécnico, Federal University of Paraná, UFPR, Jardim das Américas, CEP 81531-990, Curitiba, Paraná, Brazil
| | - A E Hamasaki
- Department of Cell Biology, Centro Politécnico, Federal University of Paraná, UFPR, Jardim das Américas, CEP 81531-990, Curitiba, Paraná, Brazil
| | - F H Matsubara
- Department of Cell Biology, Centro Politécnico, Federal University of Paraná, UFPR, Jardim das Américas, CEP 81531-990, Curitiba, Paraná, Brazil
| | - M H Appel
- Department of Structural, Molecular Biology and Genetics, State University of Ponta Grossa, Ponta Grossa, Paraná, Brazil
| | - C R V Da Costa
- Department of Cell Biology, Centro Politécnico, Federal University of Paraná, UFPR, Jardim das Américas, CEP 81531-990, Curitiba, Paraná, Brazil
| | - R Amson
- Institute Gustave Roussy, Unité Inserm U981, Bâtiment B2M, Villejuif, France
| | - A Telerman
- Institute Gustave Roussy, Unité Inserm U981, Bâtiment B2M, Villejuif, France
| | - O M Chaim
- Department of Cell Biology, Centro Politécnico, Federal University of Paraná, UFPR, Jardim das Américas, CEP 81531-990, Curitiba, Paraná, Brazil
| | - S S Veiga
- Department of Cell Biology, Centro Politécnico, Federal University of Paraná, UFPR, Jardim das Américas, CEP 81531-990, Curitiba, Paraná, Brazil
| | - A Senff-Ribeiro
- Department of Cell Biology, Centro Politécnico, Federal University of Paraná, UFPR, Jardim das Américas, CEP 81531-990, Curitiba, Paraná, Brazil
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Radin DP, Patel P. A current perspective on the oncopreventive and oncolytic properties of selective serotonin reuptake inhibitors. Biomed Pharmacother 2017; 87:636-639. [DOI: 10.1016/j.biopha.2017.01.024] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 12/29/2016] [Accepted: 01/03/2017] [Indexed: 11/17/2022] Open
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