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Cui J, Ma N, Li X, Chen X, Zhang J, Zhang W, Li H. Morphine Contributes to Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer Cells by Blocking COX-2 Methylation via Regulating the miR-23a-3p/DNMT3A Feedback. Cell Biochem Biophys 2025:10.1007/s12013-025-01749-8. [PMID: 40227561 DOI: 10.1007/s12013-025-01749-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2025] [Indexed: 04/15/2025]
Abstract
To investigate the effects and mechanisms of morphine on epithelial-mesenchymal transformation (EMT) in triple-negative breast cancer (TNBC). The levels of miR-23a-3p, DNMT3A, and COX-2 in tumor tissues from metastatic TNBC patients treated with morphine were assessed using qRT-PCR. Functional assays assessed morphine's impact on TNBC cell malignancy. Dual luciferase reporter and RNA pull-down assays investigated the interaction between miR-23a-3p and DNMT3A. miR-23a-3p inhibitor and DNMT3A siRNA were transfected into TNBC cells. Protein expression was analyzed by Western blot. Methylation status of miR-23a-3p and COX-2 was assessed via methylation-specific PCR. Rescue experiments were performed to research whether morphine modulates EMT in TNBC through COX-2 methylation regulation via the miR-23a-3p/DNMT3A feedback loop. The effects of morphine on TNBC in nude mice xenotransplantation were studied. In metastatic TNBC patients treated with morphine, miR-23a-3p and COX-2 expression were elevated, and DNMT3A levels were reduced. In TNBC cells, morphine enhanced migration, invasion, and EMT, and suppressed apoptosis. It upregulated miR-23a-3p and COX-2; downregulated DNMT3A; and inhibited methylation of miR-23a-3p and COX-2. miR-23a-3p directly inhibited DNMT3A expression. In morphine-treated TNBC cells, silencing DNMT3A reduced methylation of miR-23a-3p and COX-2. miR-23a-3p inhibitor suppressed migration, invasion, and EMT, and promoted apoptosis; however, these effects were reversed by DNMT3A silencing. In vivo, morphine promoted tumor EMT and metastasis in TNBC; reduced miR-23a-3p and COX-2 methylation; and decreased DNMT3A expression. Morphine accelerated EMT in TNBC by inhibiting COX-2 methylation through the miR-23a-3p/DNMT3A loop.
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Affiliation(s)
- Jian Cui
- Department of Anaesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Province, China
| | - Nina Ma
- Department of Anaesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Province, China
| | - Xiaohui Li
- Department of Anaesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Province, China
| | - Xuexin Chen
- Department of Anaesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Province, China
| | - Junxia Zhang
- Ningxia Medical University, Yinchuan, Ningxia Province, China
| | - Wenjuan Zhang
- Ningxia Medical University, Yinchuan, Ningxia Province, China
| | - Hong Li
- Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Province, China.
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Bezu L, Forget P, Hollmann MW, Parat MO, Piegeler T. Potential influence of different peri-operative analgesic regimens on tumour biology and outcome after oncologic surgery: A narrative review. Eur J Anaesthesiol 2025; 42:233-243. [PMID: 39743967 DOI: 10.1097/eja.0000000000002118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The management of peri-operative pain is one of the pillars of anaesthesia and is of particular importance in patients undergoing surgery for solid malignant tumours. Amongst several options, the most commonly employed analgesic regimens involve opioids, NSAIDs and regional anaesthesia techniques with different local anaesthetics. In recent years, several research reports have tried to establish a connection between peri-operative anaesthesia care and outcome after cancer surgery. Experimental studies have indicated that certain pain management substances may influence cancer progression, mainly by modifying the tumour's response to surgical stress and peri-operative inflammation. However, these promising in-vitro and in-vivo data have yet to be confirmed by randomised clinical trials. The reason for this might lie with the nature of tumour biology itself, and in the diversity of patient and tumour phenotypes. In a translational approach, future research should therefore concentrate on patient and tumour-related factors or biomarkers, which might either influence the tumour and its microenvironment or predict potential responses to interventions, including the choice of the analgesic. This might not only be relevant for the daily practice of clinical anaesthesia, but would also be of great importance for patients undergoing cancer surgery, who might be able to receive an individualised anaesthetic regimen based on their phenotypic profile.
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Affiliation(s)
- Lucillia Bezu
- From the Département d'Anesthésie, Chirurgie et Interventionnel (LB), U1138 Metabolism, Cancer and Immunity, Gustave Roussy, Villejuif, France (LB), Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, California, USA (LB), Aberdeen Centre for Arthritis and Musculoskeletal Health (Epidemiology Group), Institute of Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition (PF), Anaesthesia department, NHS Grampian, Aberdeen, UK (PF), IMAGINE UR UM 103, Montpellier University, Anesthesia Critical Care, Emergency and Pain Medicine Division, Nîmes University Hospital, Nîmes, France (PF), Pain and Opioids after Surgery (PANDOS) European Society of Anaesthesiology and Intensive Care (ID ESAIC_RG_PAND) Research Group, Brussels, Belgium (PF), Department of Anaesthesiology, Amsterdam UMC, Amsterdam, The Netherlands (MWH), School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba Qld, Australia (M-OP), Department of Anaesthesiology and Intensive Care, University of Leipzig Medical Center, Leipzig, Germany (TP), EuroPeriscope, ESAIC Onco-Anaesthesiology Research Group, Brussels, Belgium (TP, LB, PF, MWH)
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Zhang Y, Liu Y, Chen K, Miao Q, Cao Q, Zhang X. Exploring the Effects of Opioid-Related Drugs on the Clinical Outcome of Prostate Cancer Patients Via Integrated Bioinformatics Analysis. Mol Biotechnol 2025:10.1007/s12033-024-01353-w. [PMID: 39832058 DOI: 10.1007/s12033-024-01353-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 12/07/2024] [Indexed: 01/22/2025]
Abstract
Opioids are the primary regimens for perioperative analgesia with controversial effects on oncological survival. The underlying mechanism remains unexplored. This study developed survival-related gene co-expression networks based on RNA-seq and clinical characteristics from TCGA cohort. Two survival-related networks were identified, and drug-induced transcriptional profiles were predicted. Immune cell infiltration algorithm, least absolute shrinkage and selection operator (LASSO) regression, and cox proportional models were executed to explore the correlation between opioid-related drugs and prostate cancer patient prognosis. The opioid receptor agonists, represented by tramadol, were evidenced for anti-survival effects on prostate cancer by facilitating the DNA replication and cell cycle, and immune cell infiltration. Conversely, opioid receptor antagonists showed pro-survival effects. A novel prognostic model containing CNIH2, MCCC1, and Gleason scores was established and validated in two independent cohorts. This study revealed opioids' effect on prostate cancer progression, and provided a novel model to predict these regulations in clinical outcomes.
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Affiliation(s)
- Yunxuan Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuenan Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kailei Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Miao
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Cao
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xiaoping Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China.
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Pinheiro AV, Petrucci GN, Dourado A, Silva F, Pires I. Pain Management in Animals with Oncological Disease: Opioids as Influencers of Immune and Tumor Cellular Balance. Cancers (Basel) 2024; 16:3015. [PMID: 39272873 PMCID: PMC11394036 DOI: 10.3390/cancers16173015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/07/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Advancements in understanding pain physiopathology have historically challenged animals' absence of pain senses. Studies have demonstrated that animals have comparable neural pain pathways, suggesting that cats and dogs likely experience pain similarly to humans. Understanding brain circuits for effective pain control has been crucial to adjusting pain management to the patient's individual responses and current condition. The refinement of analgesic strategies is necessary to better cater to the patient's demands. Cancer pain management searches to ascertain analgesic protocols that enhance patient well-being by minimizing or abolishing pain and reducing its impact on the immune system and cancer cells. Due to their ability to reduce nerve sensitivity, opioids are the mainstay for managing moderate and severe acute pain; however, despite their association with tumor progression, specific opioid agents have immune-protective properties and are considered safe alternatives to analgesia for cancer patients.
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Affiliation(s)
- Ana Vidal Pinheiro
- Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
- Animal and Veterinary Department, University Institute of Health Sciences, Advanced Polytechnic and University Cooperative, CRL, 4585-116 Gandra, Portugal
- School of Agrarian Sciences, Polytechnic Institute of Viana do Castelo, Refoidos do Lima, 4990-706 Ponte de Lima, Portugal
| | - Gonçalo N Petrucci
- Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Animal and Veterinary Department, University Institute of Health Sciences, Advanced Polytechnic and University Cooperative, CRL, 4585-116 Gandra, Portugal
- Onevetgroup Hospital Veterinário do Porto (HVP), 4250-475 Porto, Portugal
- Center for Investigation Vasco da Gama (CIVG), Department of Veterinary Sciences, Vasco da Gama University School (EUVG), 3020-210 Coimbra, Portugal
| | - Amândio Dourado
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
- Onevetgroup Hospital Veterinário do Porto (HVP), 4250-475 Porto, Portugal
| | - Filipe Silva
- Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
| | - Isabel Pires
- Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
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Ao L, Shi J, Gan J, Yu W, Du H. Effects of dexmedetomidine and ketorolac applied for patient‑controlled analgesia on the balance of Th1/Th2 and level of VEGF in patients undergoing laparoscopic surgery for cervical cancer: A randomized controlled trial. Oncol Lett 2024; 28:379. [PMID: 38939623 PMCID: PMC11209859 DOI: 10.3892/ol.2024.14512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 05/16/2024] [Indexed: 06/29/2024] Open
Abstract
The aim of the present study was to explore the effects of dexmedetomidine (DEX) combined with ketorolac on postoperative patient-controlled analgesia (PCA), the balance of Th1/Th2 and the level of vascular endothelial growth factor (VEGF) in patients with cervical cancer following laparoscopic radical surgery. A total of 70 women with cervical cancer undergoing laparoscopic radical hysterectomy were enrolled in the study to randomly receive postoperative dexmedetomidine combined with ketorolac analgesia (DK group) and postoperative sufentanil analgesia (SUF group). The primary outcomes were the serum levels of interleukin-4 (IL-4), interferon-γ (IFN-γ) and VEGF, and the IFN-γ/IL-4 ratio 30 min before induction (T0), and 24 and 48 h after surgery. Secondary outcomes included numerical rating scale scores at 0 h (T0), 4 h (T1), 12 h (T2), 24 h (T3) and 48 h (T4) postoperatively, cumulative times of rescue analgesia, as well as the incidence of postoperative side effects within 48 h from surgery. Patients in the DK group reported similar analgesic effects as patients in the SUF group at T2, T3 and T4, and the incidence of postoperative nausea and vomiting was significantly lower in the DK group. In the DK group, the serum concentration of IFN-γ and IFN-γ/IL-4 ratio at 24 and 48 h after surgery were higher compared with those in the SUF group. Conversely, the serum concentrations of IL-4 at 24 h after surgery and VEGF at 24 and 48 h after surgery were significantly lower. The results indicated that the combination of DEX and ketorolac for PCA significantly improved postoperative pain and decreased the serum level of VEGF, which are associated with tumor angiogenesis. In addition, it maintained the homeostasis of postoperative immune dysfunction of patients with cervical cancer by shifting the balance between type 1 T helper cells and type 2 T helper cell (Th1/Th2 balance) to Th1 (registration no. ChiCTR1900027979; December 7, 2019).
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Affiliation(s)
- Li Ao
- Department of Anesthesiology, The First Central Clinical School, Tianjin Medical University, Tianjin 300192, P.R. China
- Department of Anesthesiology, Tangshan Maternity and Child Healthcare Hospital, Tangshan, Hebei 063000, P.R. China
| | - Jinlin Shi
- Department of Anesthesiology, Tangshan People's Hospital and Tangshan Cancer Hospital, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
| | - Jianhui Gan
- Department of Anesthesiology, Tangshan People's Hospital and Tangshan Cancer Hospital, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
| | - Wenli Yu
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Hongyin Du
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, P.R. China
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Sah D, Shoffel-Havakuk H, Tsur N, Uhelski ML, Gottumukkala V, Cata JP. Opioids and Cancer: Current Understanding and Clinical Considerations. Curr Oncol 2024; 31:3086-3098. [PMID: 38920719 PMCID: PMC11203256 DOI: 10.3390/curroncol31060235] [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: 05/03/2024] [Revised: 05/23/2024] [Accepted: 05/29/2024] [Indexed: 06/27/2024] Open
Abstract
Pain is one of the most common symptoms in patients with cancer. Pain not only negatively affects the quality of life of patients with cancer, but it has also been associated with reduced survival. Pain management is therefore a critical component of cancer care. Prescription opioids remain the first-line approach for the management of moderate-to-severe pain associated with cancer. However, there has been increasing interest in understanding whether these analgesics could impact cancer progression. Furthermore, epidemiological data link a possible association between prescription opioid usage and cancer development. Until more robust evidence is available, patients with cancer with moderate-to-severe pain may receive opioids to decrease suffering. However, future studies should be conducted to evaluate the role of opioids and opioid receptors in specific cancers.
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Affiliation(s)
- Dhananjay Sah
- Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.S.); (V.G.)
- Anesthesiology and Surgical Oncology Research Group (ASORG), Houston, TX 77030, USA
| | - Hagit Shoffel-Havakuk
- Department of Otolaryngology-Head and Neck Surgery, Rabin Medical Center, Petach Tiqva 4941492, Israel; (H.S.-H.); (N.T.)
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Nir Tsur
- Department of Otolaryngology-Head and Neck Surgery, Rabin Medical Center, Petach Tiqva 4941492, Israel; (H.S.-H.); (N.T.)
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Megan L. Uhelski
- Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Vijaya Gottumukkala
- Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.S.); (V.G.)
| | - Juan P. Cata
- Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.S.); (V.G.)
- Anesthesiology and Surgical Oncology Research Group (ASORG), Houston, TX 77030, USA
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Kupnicka P, Listos J, Tarnowski M, Kolasa A, Kapczuk P, Surówka A, Kwiatkowski J, Janawa K, Chlubek D, Baranowska-Bosiacka I. The Effect of Prenatal and Neonatal Fluoride Exposure to Morphine-Induced Neuroinflammation. Int J Mol Sci 2024; 25:826. [PMID: 38255899 PMCID: PMC10815549 DOI: 10.3390/ijms25020826] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 01/01/2024] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
Physical dependence is associated with the formation of neuroadaptive changes in the central nervous system (CNS), both at the molecular and cellular levels. Various studies have demonstrated the immunomodulatory and proinflammatory properties of morphine. The resulting neuroinflammation in drug dependence exacerbates substance abuse-related behaviors and increases morphine tolerance. Studies prove that fluoride exposure may also contribute to the development of neuroinflammation and neurodegenerative changes. Morphine addiction is a major social problem. Neuroinflammation increases tolerance to morphine, and neurodegenerative effects caused by fluoride in structures related to the development of dependence may impair the functioning of neuronal pathways, change the concentration of neurotransmitters, and cause memory and learning disorders, which implies this element influences the development of dependence. Therefore, our study aimed to evaluate the inflammatory state of selected brain structures in morphine-dependent rats pre-exposed to fluoride, including changes in cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) expression as well as microglial and astroglial activity via the evaluation of Iba1 and GFAP expression. We provide evidence that both morphine administration and fluoride exposure have an impact on the inflammatory response by altering the expression of COX-1, COX-2, ionized calcium-binding adapter molecule (Iba1), and glial fibrillary acidic protein (GFAP) in brain structures involved in dependence development, such as the prefrontal cortex, striatum, hippocampus, and cerebellum. We observed that the expression of COX-1 and COX-2 in morphine-dependent rats is influenced by prior fluoride exposure, and these changes vary depending on the specific brain region. Additionally, we observed active astrogliosis, as indicated by increased GFAP expression, in all brain structures of morphine-dependent rats, regardless of fluoride exposure. Furthermore, the effect of morphine on Iba1 expression varied across different brain regions, and fluoride pre-exposure may influence microglial activation. However, it remains unclear whether these changes are a result of the direct or indirect actions of morphine and fluoride on the factors analyzed.
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Affiliation(s)
- Patrycja Kupnicka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Joanna Listos
- Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland
| | - Maciej Tarnowski
- Department of Physiology in Health Sciences, Pomeranian Medical University, 70-210 Szczecin, Poland
| | - Agnieszka Kolasa
- Department of Histology and Embryology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Patrycja Kapczuk
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Anna Surówka
- Department of Plastic, Endocrine and General Surgery, Pomeranian Medical University, 72-010 Szczecin, Poland
| | - Jakub Kwiatkowski
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Kamil Janawa
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
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Silva A, Costa B, Castro I, Mourão J, Vale N. New Perspective for Drug-Drug Interaction in Perioperative Period. J Clin Med 2023; 12:4810. [PMID: 37510925 PMCID: PMC10381519 DOI: 10.3390/jcm12144810] [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: 06/03/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
In this review, we aim to discuss current information on drug interactions in the perioperative period. During this period, patients receive several drugs that may interact with each other and affect the efficacy and safety of the treatment. There are three types of drug interactions: pharmacodynamic, pharmacokinetic, and pharmaceutical. It is important to recognize that drug interactions may increase the toxicity of the drug or reduce its efficacy, increasing the risk of complications in the perioperative period. This review describes the most commonly used perioperative drugs approved by the FDA and some of the described interactions between them. Thoroughly reviewing a patient's medication list and identifying potential interactions are essential steps in minimizing risks. Additionally, vigilant monitoring of patients during and after surgery plays a pivotal role in early detection of any signs of drug interactions. This article emphasizes the significance of addressing DDIs in the perioperative period to ensure patient well-being and advocates for the implementation of careful monitoring protocols to promptly identify and manage potential interactions.
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Affiliation(s)
- Abigail Silva
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Bárbara Costa
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Irene Castro
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Department of Anesthesiology and Intensive Care Medicine, Instituto Português de Oncologia do Porto (IPO-Porto), 4200-072 Porto, Portugal
| | - Joana Mourão
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Anesthesiology, Centro Hospitalar Universitário de São João, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Surgery and Physiology Department, Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
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Desjardins P, Ménassa M, Desbiens F, Gagné JP, Hogue JC, Poirier É. Effect of single-shot intrathecal morphine versus continuous epidural analgesia on length of stay after gastrectomy for cancer: a retrospective cohort study. Gastric Cancer 2023; 26:648-652. [PMID: 37017792 DOI: 10.1007/s10120-023-01386-1] [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: 06/02/2022] [Accepted: 03/24/2023] [Indexed: 04/06/2023]
Abstract
BACKGROUND Single-dose intrathecal opiates (ITO) could shorten the length of hospital stay compared to thoracic epidural analgesia (TEA). This study aimed to compare TEA with TIO in terms of length of hospital stay, pain control, and parenteral opioid consumption in patients undergoing gastrectomy for cancer. METHODS The patients who underwent gastrectomy for cancer in 2007-2018 at the CHU de Québec-Université Laval were included. The patients were grouped as TEA and intrathecal morphine (ITM). The primary outcome was the length of hospital of stay (LOS). The secondary outcomes were numeric rating scales (NRS) for pain and parenteral opioid consumption. RESULTS A total of 79 patients were included. There were no differences in preoperative characteristics between the two groups (all P > 0.05). The median LOS was shorter in the ITM group than in the TEA group (median, 7.5 vs. 10 days, P = 0.049). The opioids consumption at 12, 24, and 48 h postoperatively was significantly lower in the TEA group at all time points. The NRS score for pain was lower in the TEA group than in the ITM group at all time points (all P < 0.05). CONCLUSIONS Patients with ITM analgesia undergoing gastrectomy presented shorter LOS than those with TEA. ITM had an inferior pain control that did not have a clinical impact on recovery in the cohort studied. Given the limitations of this retrospective study, further trials are warranted.
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Affiliation(s)
- Philippe Desjardins
- Département d'Anesthésiologie, Quebec City, QC, Canada
- CHU de Québec, Université Laval, 10 Rue de L'Espinay, Québec, QC, G1L 3L5, Canada
| | | | | | - Jean-Pierre Gagné
- Département de Chirurgie, Faculté de Médecine, Université Laval, Pavillon Ferdinand-Vandry, 1050 Ave de La Médecine, Quebec City, QC, G1V 0A6, Canada
- CHU de Québec, Université Laval, 10 Rue de L'Espinay, Québec, QC, G1L 3L5, Canada
| | - Jean-Charles Hogue
- Axe Oncologie, Centre de Recherche du CHU de Québec, Université Laval, 1050 Chemin Ste-Foy, Québec City, QC, G1S 4L8, Canada
| | - Éric Poirier
- Département de Chirurgie, Faculté de Médecine, Université Laval, Pavillon Ferdinand-Vandry, 1050 Ave de La Médecine, Quebec City, QC, G1V 0A6, Canada.
- CHU de Québec, Université Laval, 10 Rue de L'Espinay, Québec, QC, G1L 3L5, Canada.
- Axe Oncologie, Centre de Recherche du CHU de Québec, Université Laval, 1050 Chemin Ste-Foy, Québec City, QC, G1S 4L8, Canada.
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10
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Constance JE, McFarland MM, Casucci T, Deininger MW, Enioutina EY, Job K, Lemons RS, Lim CS, Ward RM, Yellepeddi V, Watt KM. Mapping the Evidence for Opioid-Mediated Changes in Malignancy and Chemotherapeutic Efficacy: Protocol for a Scoping Review. JMIR Res Protoc 2023; 12:e38167. [PMID: 37213193 PMCID: PMC10242459 DOI: 10.2196/38167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 03/19/2023] [Accepted: 04/05/2023] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND Numerous reports contend opioids can augment or inhibit malignancy. At present, there is no consensus on the risk or benefit posed by opioids on malignancy or chemotherapeutic activity. Distinguishing the consequences of opioid use from pain and its management is challenging. Additionally, opioid concentration data is often lacking in clinical studies. A scoping review approach inclusive of preclinical and clinical data will improve our understanding of the risk-benefit relationship concerning commonly prescribed opioids and cancer and cancer treatment. OBJECTIVE The aim of the study is to map diverse studies spanning from preclinical to clinical regarding opioids with malignancy and its treatment. METHODS This scoping review will use the Arksey six stages framework to (1) identify the research question; (2) identify relevant studies; (3) select studies meeting criteria; (4) extract and chart data; (5) collate, summarize, and report results; and (6) conduct expert consultation. An initial pilot study was undertaken to (1) parameterize the extent and scale of existing data for an evidence review, (2) identify key factors to be extracted in systematic charting efforts, and (3) assess opioid concentration as a variable for its relevance to the central hypothesis. Six databases will be searched with no filters: MEDLINE, Embase, CINAHL Complete, Cochrane Library, Biological Sciences Collection, and International Pharmaceutical Abstracts. Trial registries will include ClinicalTrials.gov, Cochrane CENTRAL, International Standard Randomised Controlled Trial Number Registry, European Union Clinical Trials Register, and World Health Organization International Clinical Trials Registry. Eligibility criteria will include preclinical and clinical study data on opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will chart data on (1) opioid concentration from human subjects with cancer, yielding a "physiologic range" to better interpret available preclinical data; (2) patterns of opioid exposure with disease and treatment-related patient outcomes; and (3) the influence of opioids on cancer cell survival, as well as opioid-related changes to cancer cell susceptibility for chemotherapeutics. RESULTS This scoping review will present results in narrative forms as well as with the use of tables and diagrams. Initiated in February 2021 at the University of Utah, this protocol is anticipated to generate a scoping review by August 2023. The results of the scoping review will be disseminated through scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal. CONCLUSIONS The findings of this scoping review will provide a comprehensive description of the consequences of prescription opioids on malignancy and its treatment. By incorporating preclinical and clinical data, this scoping review will invite novel comparisons across study types that could inform new basic, translational, and clinical studies regarding risks and benefits of opioid use among patients with cancer. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/38167.
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Affiliation(s)
- Jonathan E Constance
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
| | - Mary M McFarland
- Spencer S. Eccles Health Science Library, University of Utah, Salt Lake City, UT, United States
| | - Tallie Casucci
- J Willard Marriott Library, University of Utah, Salt Lake City, UT, United States
| | - Michael W Deininger
- Versiti Blood Research Institute, Milwaukee, WI, United States
- Division of Hematology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Elena Y Enioutina
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
| | - Kathleen Job
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
| | - Richard S Lemons
- Division of Hematology and Oncology, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
| | - Carol S Lim
- Department of Molecular Pharmaceutics, College of Pharmacy, University of Utah, Salt Lake City, UT, United States
| | - Robert M Ward
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
| | - Venkata Yellepeddi
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
| | - Kevin M Watt
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
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11
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Thomas TE, Bowers K, Gomez D, Morgan O, Borowsky PA, Dutta R, Abu Y, Roy S, Rojas KE. The association between perioperative opioids and breast cancer recurrence: a narrative review of the literature. TRANSLATIONAL BREAST CANCER RESEARCH : A JOURNAL FOCUSING ON TRANSLATIONAL RESEARCH IN BREAST CANCER 2023; 4:12. [PMID: 38751469 PMCID: PMC11093068 DOI: 10.21037/tbcr-23-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 04/23/2023] [Indexed: 05/18/2024]
Abstract
Background and Objective Opioid use disorder is an evolving crisis, and 17.2% of postsurgical patients continue to fill an opioid prescription one year after surgery. Preclinical studies suggest perioperative opioid use, defined here as opioids used in the setting of operative pain, may be linked to inferior oncologic outcomes. If this were true, opioid minimization strategies for surgical patients may reduce opioid-related deaths in more than one way. This review aims to describe the association between perioperative opioid use and breast cancer recurrence. Methods On November 1, 2021, we searched the Ovid and EMBASE databases for the terms "breast neoplasm", "opioid analgesics", "neoplasm recurrence", and "neoplasm metastasis". Of the 350 articles retrieved, 11 met our inclusion criteria. The review was undertaken using the enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) checklist for quality. Key Content and Findings Clinical studies report no clear association between perioperative opioid use and local or distant breast cancer recurrence. Mixed results were found when assessing perioperative opioid use and overall survival. Multiple studies paradoxically found opioid use to be associated with lower recurrence rates, despite higher mortality rates. Most studies showed no difference in recurrence or survival in breast cancer surgery patients who did or did not receive opioid-containing analgesia, although most findings were limited by study design and low event rates in patients with breast cancer. Conclusions The lack of a clear connection between perioperative opioid use and breast cancer recurrence contradicts some preclinical data, which describes mechanisms through which opioids upregulate tumor proliferation which might worsen oncologic outcomes. Existing clinical literature is limited to mostly retrospective studies in patients with predominantly early-stage breast cancers, with low event rates. Given the worsening opioid epidemic and preclinical study findings, opioid minimization strategies should still be explored. Future work should be prospective and examine cancer recurrence in high-risk patients with more advanced tumor pathologies.
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Affiliation(s)
- Tanya E. Thomas
- Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Kara Bowers
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Daniel Gomez
- Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Orly Morgan
- Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Rajib Dutta
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Yaa Abu
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sabita Roy
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kristin E. Rojas
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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12
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Brusco I, Becker G, Palma TV, Pillat MM, Scussel R, Steiner BT, Sampaio TB, Ardisson-Araújo DMP, de Andrade CM, Oliveira MS, Machado-De-Avila RA, Oliveira SM. Kinin B 1 and B 2 receptors mediate cancer pain associated with both the tumor and oncology therapy using aromatase inhibitors. Sci Rep 2023; 13:4418. [PMID: 36932156 PMCID: PMC10023805 DOI: 10.1038/s41598-023-31535-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
Pain caused by the tumor or aromatase inhibitors (AIs) is a disabling symptom in breast cancer survivors. Their mechanisms are unclear, but pro-algesic and inflammatory mediators seem to be involved. Kinins are endogenous algogenic mediators associated with various painful conditions via B1 and B2 receptor activation, including chemotherapy-induced pain and breast cancer proliferation. We investigate the involvement of the kinin B1 and B2 receptors in metastatic breast tumor (4T1 breast cancer cells)-caused pain and in aromatase inhibitors (anastrozole or letrozole) therapy-associated pain. A protocol associating the tumor and antineoplastic therapy was also performed. Kinin receptors' role was investigated via pharmacological antagonism, receptors protein expression, and kinin levels. Mechanical and cold allodynia and muscle strength were evaluated. AIs and breast tumor increased kinin receptors expression, and tumor also increased kinin levels. AIs caused mechanical allodynia and reduced the muscle strength of mice. Kinin B1 (DALBk) and B2 (Icatibant) receptor antagonists attenuated these effects and reduced breast tumor-induced mechanical and cold allodynia. AIs or paclitaxel enhanced breast tumor-induced mechanical hypersensitivity, while DALBk and Icatibant prevented this increase. Antagonists did not interfere with paclitaxel's cytotoxic action in vitro. Thus, kinin B1 or B2 receptors can be a potential target for treating the pain caused by metastatic breast tumor and their antineoplastic therapy.
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Affiliation(s)
- Indiara Brusco
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.
| | - Gabriela Becker
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil
| | - Tais Vidal Palma
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil
| | - Micheli Mainardi Pillat
- Department of Microbiology and Parasitology, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Rahisa Scussel
- Graduate Program in Health Sciences, University of Extreme South Catarinense, Criciuma, SC, Brazil
| | - Bethina Trevisol Steiner
- Graduate Program in Health Sciences, University of Extreme South Catarinense, Criciuma, SC, Brazil
| | - Tuane Bazanella Sampaio
- Graduate Program in Pharmacology, Department of Physiology and Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Daniel Mendes Pereira Ardisson-Araújo
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil
- Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasilia, DF, Brazil
| | - Cinthia Melazzo de Andrade
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil
| | - Mauro Schneider Oliveira
- Graduate Program in Pharmacology, Department of Physiology and Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | | | - Sara Marchesan Oliveira
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.
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13
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Vaseghi G, Ghasemi A, Laher I, Alaei H, Dana N, Naji esfahani H, Javanmard SH. Morphine upregulates Toll-like receptor 4 expression and promotes melanomas in mice. Immunopharmacol Immunotoxicol 2022; 45:347-354. [DOI: 10.1080/08923973.2022.2145967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Golnaz Vaseghi
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ahmad Ghasemi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ismail Laher
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
| | - HojjatAllah Alaei
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nasim Dana
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hajar Naji esfahani
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
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14
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Rezaeiamiri E, Asadi M, Hosseini FS, Amanlou A, Dehpour AR, Amanlou M. Thebaine Derivatives as a New Regulator of Tumor Angiogenesis. Polycycl Aromat Compd 2022. [DOI: 10.1080/10406638.2021.1922471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Elnaz Rezaeiamiri
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Asadi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Faezeh Sadat Hosseini
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Arash Amanlou
- Faculty of Specialized Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Massoud Amanlou
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
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15
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Santoni A, Santoni M, Arcuri E. Chronic Cancer Pain: Opioids within Tumor Microenvironment Affect Neuroinflammation, Tumor and Pain Evolution. Cancers (Basel) 2022; 14:2253. [PMID: 35565382 PMCID: PMC9104169 DOI: 10.3390/cancers14092253] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 02/04/2023] Open
Abstract
Pain can be a devastating experience for cancer patients, resulting in decreased quality of life. In the last two decades, immunological and pain research have demonstrated that pain persistence is primarily caused by neuroinflammation leading to central sensitization with brain neuroplastic alterations and changes in pain responsiveness (hyperalgesia, and pain behavior). Cancer pain is markedly affected by the tumor microenvironment (TME), a complex ecosystem consisting of different cell types (cancer cells, endothelial and stromal cells, leukocytes, fibroblasts and neurons) that release soluble mediators triggering neuroinflammation. The TME cellular components express opioid receptors (i.e., MOR) that upon engagement by endogenous or exogenous opioids such as morphine, initiate signaling events leading to neuroinflammation. MOR engagement does not only affect pain features and quality, but also influences directly and/or indirectly tumor growth and metastasis. The opioid effects on chronic cancer pain are also clinically characterized by altered opioid responsiveness (tolerance and hyperalgesia), a hallmark of the problematic long-term treatment of non-cancer pain. The significant progress made in understanding the immune-mediated development of chronic pain suggests its exploitation for novel alternative immunotherapeutic approaches.
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Affiliation(s)
- Angela Santoni
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Viale Regina Elena 291, 00161 Rome, Italy
- IRCCS Neuromed, 86077 Pozzilli, Italy
| | - Matteo Santoni
- Medical Oncology Unit, Macerata General Hospital, Via Santa Lucia 2, 62100 Macerata, Italy;
| | - Edoardo Arcuri
- IRCCS Regina Elena Cancer Institute, IFO, Via Elio Chianesi 53, 00128 Rome, Italy;
- Ars Medica Pain Clinic, Via Cesare Ferrero da Cambiano 29, 00191 Rome, Italy
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16
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Cui P, Xin D, Li F, Deng L, Gao Y. Butorphanol Suppresses the Proliferation and Migration of Osteosarcoma by Promoting the Expression of piRNA hsa_piR_006613. Front Oncol 2022; 12:775132. [PMID: 35280771 PMCID: PMC8912933 DOI: 10.3389/fonc.2022.775132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/20/2022] [Indexed: 12/21/2022] Open
Abstract
Butorphanol, a partial agonist of opioid receptor κ 1 receptor, can and is widely used as an analgesic drug to relieve moderate and severe pain in clinic. Osteosarcoma is one of the most common malignant bone tumor in adolescents under the age of 20. To our knowledge no study has investigated the effect of butorphanol on the proliferation of osteosarcoma cells. In this study, The proliferation of osteosarcoma cells was measured by CCK-8 and colony formation assays, and the migration of osteosarcoma cells were detected by scratch and transwell assays. The expression of piRNA was detected by RNA sequencing and real-time PCR. PiRNA mimics or inhibitors have been used to upregulate or inhibit piRNA expression in osteosarcoma cells, respectively. We found that butorphanol, at the concentration of 10ug/ml or higher, could significantly inhibit the proliferation and migration of osteosarcoma cells. Our resuslts indicated that butorphanol promoted the expression of piRNA hsa_piR_006613 and overexpression of piRNA hsa_piR_006613 inhibited the proliferation and migration of osteosarcoma cells. our study also showed that inhibition of the expression of piRNA hsa_piR_006613 could promote the proliferation and migration of osteosarcoma cells. Butorphanol played the regulatory role on osteosarcoma cells in dependent of piRNA hsa_piR_006613. Butorphanol was found to inhibit the proliferation and migration of osteosarcoma cells by promoting piRNA hsa_piR_006613 expression. Bioinformatics analysis showed that hsa_piR_006613 downregulated FN1 protein expression by binding with 3’-UTR of FN1 mRNA. In all, the present research indicated that butorphanol suppresses the proliferation of osteosarcoma by promoting the expression of piRNA hsa_piR_006613, which downregulated the expression of FN1. Has_piR_006613 may become a new therapeutic target for osteosarcoma.
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Affiliation(s)
- Pengfei Cui
- Department of Anesthesiology, Yantaishan Hospital, Yantai, China
| | - Deqian Xin
- Department of Anesthesiology, YanTai Yuhuangding Hospital, Yantai, China
| | - Fu Li
- Department of Traumatology, Shu Guang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lin Deng
- Department of Traumatology, Shu Guang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yujie Gao
- Department of Clinical Laboratory, YanTai Yuhuangding Hospital, Yantai, China
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17
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Edinoff AN, Derise OC, Sheppard AJ, Miriyala S, Virgen CG, Kaye AJ, Niakan M, Cornett EM, Kaye AD. The Influence of Analgesic Modalities on Postoperative Cancer Recurrence. Anesth Pain Med 2022; 12:e123463. [PMID: 35433388 PMCID: PMC8995873 DOI: 10.5812/aapm.123463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 02/20/2022] [Indexed: 11/16/2022] Open
Abstract
The potential for cancer cells to grow and to metastasize depends on complex interactions between inflammatory signals and pathways, immune cells, and elements of the stromal tissue in which they invade. Related to the nature of many cancers, the probability of recurrence can potentially be quite high for some patients. Immunology, lifestyle modifications, timing of disease, genetics, age, gender, and race are only a handful of ways the likelihood of cancer recurrence can be influenced. The quantity, or density, of certain immunological cells or factors, plays a role in the propagation of cancer cells. Opioids are often used in cancer patients for acute postoperative and chronic pain management. While they can produce significant pain relief, the type of analgesic utilized is important, as it may influence cancer propagation. In this regard, certain opioids have been found to increase T regulatory cells while suppressing NK cell function. Morphine may promote tumor neovascularization and expansion. Fentanyl administration significantly diminishes NK-cells and CD8+ cytotoxic T-cells. In a recent meta-analysis, propofol-based anesthesia improved both cancer-free survival and overall survival. COX inhibitors have also shown promise in persevering cancer immune function, as in literature involving ketorolac and celecoxib. In summary, inhaled anesthesia and opioids may contribute to a pro-tumor metastasis environment also known as cancer propagation; whereas propofol and COX inhibitors may provide a better alternative to reduce cancer recurrence and propagation.
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Affiliation(s)
- Amber N. Edinoff
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA
- Corresponding Author: Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA.
| | - Olivia C. Derise
- School of Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA
| | - Aaron J. Sheppard
- School of Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA
| | - Sumitra Miriyala
- School of Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA
| | - Celina G. Virgen
- College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Aaron J. Kaye
- Department of Anesthesiology, Medical University of South Carolina, Charleston, SC, USA
| | - Mohammad Niakan
- Pain Research Center, Department of Anesthesiology Intensive Care and Pain Medicine, Iran University of Medical Sciences, Tehran, Iran
- Corresponding Author: Pain Research Center, Department of Anesthesiology Intensive Care and Pain Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Elyse M. Cornett
- Department of Anesthesiology, Louisiana State University Shreveport, Shreveport, LA, USA
| | - Alan D. Kaye
- Department of Anesthesiology, Louisiana State University Shreveport, Shreveport, LA, USA
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18
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Vaseghi G, Dana N, Ghasemi A, Abediny R, Laher I, Javanmard SH. Morphine promotes migration and lung metastasis of mouse melanoma cells. BRAZILIAN JOURNAL OF ANESTHESIOLOGY (ELSEVIER) 2022:S0104-0014(22)00001-X. [PMID: 35121060 PMCID: PMC10362449 DOI: 10.1016/j.bjane.2021.10.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 10/11/2021] [Accepted: 10/24/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Morphine is an analgesic agent used for cancer pain management. There have been recent concerns that the immunosuppressant properties of morphine can also promote cancer metastasis. Morphine is an agonist for toll like receptor 4 (TLR4) that has a dual role in cancer development. The promotor or inhibitor role of morphine in cancer progression remains controversial. We investigated the effects of morphine on migration and metastasis of melanoma cells through TLR4 activation. METHODS Mouse melanoma cells (B16F10) were treated with only morphine (0, 0.1, 1, and 10 μM) or in combination with a TLR4 inhibitor (morphine10 μM +CLI-095 1μM) for either 12 or 24 hours. Migration of cells was analyzed by transwell migration assays. Twenty C57BL/6 male mice were inoculated with B16F10 cells via the left ventricle of the heart and then randomly divided into two groups (n = 10 each) that received either morphine (10 mg.kg-1, sub-q) or PBS injection for 21 days (control group). Animals were euthanized and their lungs removed for evaluation of metastatic nodules. RESULTS Morphine (0.1, 1, and 10 μM) increased cell migration after 12 hours (p < 0.001) and after 24 hours of treatment with morphine (10 μM) (p < 0.001). Treatment with CLI-095 suppressed migration compared to cells treated with morphine alone (p < 0.001). Metastatic nodules in the morphine-treated group (64 nodules) were significantly higher than in the control group (40 nodules) (p < 0.05). CONCLUSION Morphine increases the migration and metastasis of mouse melanoma cells by activating TLR4.
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Affiliation(s)
- Golnaz Vaseghi
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical sciences, Isfahan, Iran; Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nasim Dana
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ahmad Ghasemi
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Reza Abediny
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ismail Laher
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.
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Antonenko T, Gracheva Y, Shpakovsky D, Vorobyev M, Tafeenko V, Mazur D, Milaeva E. Cytotoxic activity of organotin compounds containing non-steroidal anti-inflammatory drugs. J Organomet Chem 2022. [DOI: 10.1016/j.jorganchem.2021.122191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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20
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Urinary PGE-M in Men with Prostate Cancer. Cancers (Basel) 2021; 13:cancers13164073. [PMID: 34439226 PMCID: PMC8391815 DOI: 10.3390/cancers13164073] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/10/2021] [Accepted: 08/10/2021] [Indexed: 01/26/2023] Open
Abstract
Simple Summary Elevated levels of urinary prostaglandin E metabolite (PGE-M), a marker of inflammation, have previously been associated with cancer incidence and metastasis. Studies investigating PGE-M in prostate cancer are lacking even though chronic inflammation is a candidate risk factor for the disease. We investigated the association of PGE-M with lethal prostate cancer. We measured PGE-M in the urine of men with prostate cancer and in men without prostate cancer (population controls). Our participants included African American and European American men. Because African American men die more frequently from prostate cancer than European American men, we investigated whether high PGE-M may contribute to the increased mortality among African American prostate cancer patients. We did not observe a relationship between PGE-M and prostate cancer aggressiveness or prostate cancer-specific mortality in our study population, neither in the combined cohort nor in the race/ethnicity stratified analysis. Interestingly, however, we observed a significant relationship between high PGE-M and all-cause mortality in African American men with prostate cancer. Yet, there was no association between high PGE-M and all-cause mortality when these men were regular aspirin users. Abstract Urinary PGE-M is a stable metabolite of prostaglandin E2 (PGE2). PGE2 is a product of the inflammatory COX signaling pathway and has been associated with cancer incidence and metastasis. Its synthesis can be inhibited by aspirin. We investigated the association of PGE-M with lethal prostate cancer in a case–control study of African American (AA) and European American men. We measured urinary PGE-M using mass-spectrometry. Samples were obtained from 977 cases and 1022 controls at the time of recruitment. We applied multivariable logistic and Cox regression modeling to examine associations of PGE-M with prostate cancer and participant survival. Median survival follow-up was 8.4 years, with 246 deaths among cases. Self-reported aspirin use over the past 5 years was assessed with a questionnaire. Race/ethnicity was self-reported. Urinary PGE-M levels did not differ between men with prostate cancer and population-based controls. We observed no association between PGE-M and aggressive disease nor prostate-cancer-specific survival. However, we observed a statistically significant association between higher (>median) PGE-M and all-cause mortality in AA cases who did not regularly use aspirin (HR = 2.04, 95% CI 1.23–3.37). Among cases who reported using aspirin, there was no association. Our study does not support a meaningful association between urinary PGE-M and prostate cancer. Moreover, PGE-M levels were not associated with aggressive prostate cancer. However, the observed association between elevated PGE-M and all-cause mortality in AA non-aspirin users reinforces the potential benefit of aspirin to reduce mortality among AA men with prostate cancer.
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Sagi V, Mittal A, Tran H, Gupta K. Pain in sickle cell disease: current and potential translational therapies. Transl Res 2021; 234:141-158. [PMID: 33711512 PMCID: PMC8217144 DOI: 10.1016/j.trsl.2021.03.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/02/2021] [Accepted: 03/06/2021] [Indexed: 12/26/2022]
Abstract
Pain is a major comorbidity of sickle cell disease (SCD). Patients with SCD may suffer from both acute and chronic pain. Acute pain is caused by recurrent and unpredictable episodes of vaso-occlusive crises (VOC), whereas the exact etiology of chronic pain is still unknown. Opioids are the mainstay for pain treatment, but the opioid epidemic has significantly altered access to prescription opioids and has brought concerns over their long-term use into the forefront, which have negatively impacted the treatment of sickle pain. Opioids remain potent analgesics but growing opioid-phobia has led to the realization of an unmet need to develop nonopioid therapies that can provide relief for severe sickle pain. This realization has contributed to the approval of 3 different drugs by the Food and Drug Administration (FDA) for the treatment of SCD, particularly to reduce VOC and/or have an impact on the pathobiology of SCD. In this review, we outline the challenges and need for validation of side-effects of opioids and provide an update on the development of mechanism-based translational therapies, specifically targeting pain in SCD.
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Affiliation(s)
- Varun Sagi
- School of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Aditya Mittal
- School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Huy Tran
- School of Medicine, Kansas City University, Joplin, Missouri
| | - Kalpna Gupta
- Hematology/Oncology, Department of Medicine, University of California, Irvine and Southern California Institute for Research and Education, VA Medical Center, Long Beach, California.
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22
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Alagumuthu M, Srivastava V, Shah M, Arumugam S, Sonaimuthu M, Arumugam NA. Pro- and Anti-Inflammatory Cytokine Expression Levels in Macrophages; An Approach to Develop Indazolpyridin-Methanones as a Novel Inflammation Medication. Antiinflamm Antiallergy Agents Med Chem 2021; 19:425-435. [PMID: 31878864 PMCID: PMC7579299 DOI: 10.2174/1871523019666191226104724] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/16/2019] [Accepted: 12/01/2019] [Indexed: 01/01/2023]
Abstract
Background: Macrophages play a serious part in the instigation, upkeep, and resolution of inflammation. They are activated or deactivated during inflammation progression. Activation signals include cytokines (IF-γ, granulocyte-monocyte colony-stimulating factor (GM-CSF), and TNF-α), extracellular matrix proteins, and other chemical mediators. Activated macrophages are deactivated by anti-inflammatory cytokines (IL-10 and TGF-β (transforming growth factor-beta) and cytokine antagonists that are mainly produced by macrophages. Based on this, the present study aimed to develop novel (E)-Benzylidene-indazolpyridin methanones (Cpd-1-10) as effective anti-inflammatory agents by analyzing pro- and anti-inflammatory cytokine levels in macrophages. Objectives: To determine the anti-inflammatory effect of indazolpyridin-methanones by examining pro- and anti-inflammatory interleukin levels in J77A.1 macrophages. Methods: Expression of cytokines such as TNF-α, IL-1β, IL-6 and IL-10 serum levels measured by ELISA method. Anti-cancer and cytotoxicity studies were carried out by MTT assay. COX-2 seems to be associated with cancers and atypical developments in the duodenal tract. So, a competitive ELISA based COX-2 inhibition assay was done. To validate the inhibitory potentials and to get more insight into the interaction of COX-2 with Cpd1-10, molecular docking was performed. Results: Briefly, the COX-2 inhibitory relative activity was found to be in between the range of 80-92% (Diclofenac showed 84%, IC50 0.95 µM). Conclusion: Cytotoxicity effect of the compounds against breast cancer cell lines found excellent and an extended anticancer study ensured that these compounds are also alternative therapeutic agents against breast cancer. Among all the tested cancer cell lines, the anti-cancer effect on breast cancer was exceptional for the most active compounds Cpd5 and Cpd9.
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Affiliation(s)
| | | | - Manisha Shah
- School of Bio-Science & Technology, VIT University, Vellore-632014, India
| | - Sivakumar Arumugam
- School of Bio-Science & Technology, VIT University, Vellore-632014, India
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23
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Ackerman RS, Luddy KA, Icard BE, Piñeiro Fernández J, Gatenby RA, Muncey AR. The Effects of Anesthetics and Perioperative Medications on Immune Function: A Narrative Review. Anesth Analg 2021; 133:676-689. [PMID: 34100781 DOI: 10.1213/ane.0000000000005607] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Preclinical and clinical studies have sought to better understand the effect of anesthetic agents, both volatile and intravenous, and perioperative adjuvant medications on immune function. The immune system has evolved to incorporate both innate and adaptive components, which are delicately interwoven and essential for host defense from pathogens and malignancy. This review summarizes the complex and nuanced relationship that exists between each anesthetic agent or perioperative adjuvant medication studied and innate and adaptive immune function with resultant clinical implications. The most commonly used anesthetic agents were chosen for review including volatile agents (sevoflurane, isoflurane, desflurane, and halothane), intravenous agents (propofol, ketamine, etomidate, and dexmedetomidine), and perioperative adjuvant medications (benzodiazepines, opioids, nonsteroidal anti-inflammatory drugs [NSAIDs], and local anesthetic agents). Patients who undergo surgery experience varying combinations of the aforementioned anesthetic agents and adjuncts, depending on the type of surgery and their comorbidities. Each has unique effects on immunity, which may be more or less ideal depending on the clinical situation. Further study is needed to better understand the clinical effects of these relationships so that patient-specific strategies can be developed to improve surgical outcomes.
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Affiliation(s)
- Robert S Ackerman
- From the Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | | | - Benjamin E Icard
- University of South Florida Morsani College of Medicine, Tampa, Florida
| | | | - Robert A Gatenby
- the Department of Cancer Biology and Evolution.,Department of Radiology
| | - Aaron R Muncey
- Department of Anesthesiology, H. Lee Moffitt Cancer Center, Tampa, Florida
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24
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Morin C, Patel Y, Javid M, Tevis SE, Fortes T, Flom P, Andaz C, Manasseh DM, Borgen P, Rojas KE. Opioid-Sparing Multimodal Analgesia Protocol for Lumpectomy Patients Results in Superior Postoperative Pain Control. Ann Surg Oncol 2021; 28:5855-5864. [PMID: 34076809 PMCID: PMC8170864 DOI: 10.1245/s10434-021-09963-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/03/2021] [Indexed: 11/27/2022]
Abstract
Background We sought to determine if lumpectomy patients who received perioperative opioid-sparing multimodal analgesia reported less pain when compared with those who received traditional opioid-based care. Study Design A prospective cohort of patients undergoing lumpectomy who received an opioid-sparing multimodal analgesia protocol [no opioids group (NOP)] was compared with a large cohort of patients who received traditional care [opioids group (OG)]. In-hospital and discharge opioids were compared using oral morphine equivalents (OMEs). Postoperative day one and week one pain scores were compared using the Kruskal–Wallis test. Results Overall, 1153 patients underwent lumpectomy: 634 patients received the protocol (NOP), and 519 patients did not (OG). Median pain scores were significantly lower in the NOP cohort when compared with the OG cohort the day after surgery (2 vs. 0, p < 0.001) and the week after surgery (1 vs. 0, p < 0.001). NOP patients were significantly less likely to report severe pain (7–10 on a 10-point scale) the day after surgery compared with OG patients (15.7% vs. 6.9%, p = 0.004). Patients in the NOP cohort were discharged with a median of zero OMEs (range 0–150), while patients in the OG were discharged with a median of 90 OMEs (range 0–360; p < 0.001). Conclusion Implementation of an opioid-sparing multimodal analgesia protocol for lumpectomy patients resulted in superior pain control without a routine opioid prescription. Surgeons can improve their own patients’ outcomes while addressing the larger societal issue of the opioid crisis by adopting similar protocols that decrease the quantity of opioids available for diversion.
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Affiliation(s)
- Claudya Morin
- Department of Surgery, Maimonides Medical Center, Brooklyn, NY, USA
| | - Yamini Patel
- Department of Surgery, Maimonides Medical Center, Brooklyn, NY, USA
| | - Munazza Javid
- Department of Surgery, Maimonides Medical Center, Brooklyn, NY, USA
| | - Sarah E Tevis
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | | | - Peter Flom
- Peter Flom Statistical Consulting, New York City, NY, USA
| | | | | | - Patrick Borgen
- Department of Surgery, Maimonides Medical Center, Brooklyn, NY, USA.
| | - Kristin E Rojas
- Dewitt-Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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26
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27
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Tripolt S, Neubauer HA, Knab VM, Elmer DP, Aberger F, Moriggl R, Fux DA. Opioids drive breast cancer metastasis through the δ-opioid receptor and oncogenic STAT3. Neoplasia 2021; 23:270-279. [PMID: 33465556 PMCID: PMC7815495 DOI: 10.1016/j.neo.2020.12.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 12/25/2020] [Accepted: 12/29/2020] [Indexed: 11/25/2022]
Abstract
The opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental evidence exists. Expression of δ-opioid receptors (DORs) correlates with poor prognosis for breast cancer patients, but mechanistic insights into oncogenic signaling mechanisms of opioid-triggered cancer progression are lacking. We show that orthotopic transplant models using human or murine breast cancer cells displayed enhanced metastasis upon opioid-induced DOR stimulation. Interestingly, opioid-exposed breast cancer cells showed enhanced migration and strong STAT3 activation, which was efficiently blocked by a DOR-antagonist. Furthermore, opioid treatment resulted in down-regulation of E-Cadherin and increased expression of epithelial-mesenchymal transition markers. Notably, STAT3 knockdown or upstream inhibition through the JAK1/2 kinase inhibitor ruxolitinib prevented opioid-induced breast cancer cell metastasis and migration in vitro and in vivo. We conclude on a novel mechanism whereby opioid-triggered breast cancer metastasis occurs via oncogenic JAK1/2-STAT3 signaling to promote epithelial-mesenchymal transition. These findings emphasize the importance of selective and restricted opioid use, as well as the need for safer pain medication that does not activate these oncogenic pathways.
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MESH Headings
- Analgesics, Opioid/pharmacology
- Animals
- Biomarkers
- Breast Neoplasms/etiology
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cell Line, Tumor
- Disease Models, Animal
- Disease Susceptibility
- Female
- Gene Expression
- Humans
- Immunohistochemistry
- Mice
- Mice, Transgenic
- Neoplasm Metastasis
- Oncogene Proteins/metabolism
- Receptors, Opioid, delta/agonists
- Receptors, Opioid, delta/genetics
- Receptors, Opioid, delta/metabolism
- STAT3 Transcription Factor/metabolism
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Affiliation(s)
- Sabrina Tripolt
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Heidi A Neubauer
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Vanessa M Knab
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Dominik P Elmer
- Department of Biosciences, Cancer Cluster Salzburg, Paris-Lodron University of Salzburg, Salzburg, Austria
| | - Fritz Aberger
- Department of Biosciences, Cancer Cluster Salzburg, Paris-Lodron University of Salzburg, Salzburg, Austria
| | - Richard Moriggl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Daniela A Fux
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
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28
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Argueta DA, Aich A, Lei J, Kiven S, Nguyen A, Wang Y, Gu J, Zhao W, Gupta K. β-endorphin at the intersection of pain and cancer progression: Preclinical evidence. Neurosci Lett 2020; 744:135601. [PMID: 33387660 DOI: 10.1016/j.neulet.2020.135601] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 12/20/2022]
Abstract
We examined the association between endogenous opioid β-endorphin, cancer progression and pain in a transgenic mouse model of breast cancer, with a rat C3(1) simian virus 40 large tumor antigen fusion gene (C3TAg). C3TAg mice develop ductal epithelial atypia at 8 weeks, progression to intra-epithelial neoplasia at 12 weeks, and invasive carcinoma with palpable tumors at 16 weeks. Consistent with invasive carcinoma at 4 months of age, C3TAg mice demonstrate a significant increase in hyperalgesia compared to younger C3TAg or control FVBN mice without tumors. Our data show that the growing tumor contributes to circulating β-endorphin. As an endogenous ligand of mu opioid receptor, β-endorphin has analgesic activity. Paradoxically, we observed an increase in pain in transgenic breast cancer mice with significantly high circulating and tumor-associated β-endorphin. Increased circulating β-endorphin correlates with increasing tumor burden. β-endorphin induced the activation of mitogenic and survival-promoting signaling pathways, MAPK/ERK 1/2, STAT3 and Akt, observed by us in human MDA-MB-231 cells suggesting a role for β-endorphin in breast cancer progression and associated pain.
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Affiliation(s)
- Donovan A Argueta
- Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA
| | - Anupam Aich
- Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA
| | - Jianxun Lei
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Stacy Kiven
- Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA
| | - Aithanh Nguyen
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Ying Wang
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Department of Anesthesia, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Joshua Gu
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, CA, USA
| | - Weian Zhao
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, CA, USA; Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA; Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, CA, USA; Department of Biomedical Engineering, University of California, Irvine, CA, USA
| | - Kalpna Gupta
- Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA; Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Southern California Institute for Research and Education, VA Medical Center, Long Beach, CA, USA.
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Havidich JE, Weiss JE, Onega TL, Low YH, Goodrich ME, Davis MA, Sites BD. The association of prescription opioid use with incident cancer: A Surveillance, Epidemiology, and End Results-Medicare population-based case-control study. Cancer 2020; 127:1648-1657. [PMID: 33370446 DOI: 10.1002/cncr.33285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/26/2020] [Accepted: 09/01/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Cancer is the second leading cause of death globally, and researchers seek to identify modifiable risk factors Over the past several decades, there has been ongoing debate whether opioids are associated with cancer development, metastasis, or recurrence. Basic science, clinical, and observational studies have produced conflicting results. The authors examined the association between prescription opioids and incident cancers using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. A complex relation was observed between prescription opioids and incident cancer, and cancer site may be an important determinant. METHODS By using linked SEER cancer registry and Medicare claims from 2008 through 2013, a case-control study was conducted examining the relation between cancer onset and prior opioid exposure. Logistic regression was used to account for differences between cases and controls for 10 cancer sites. RESULTS Of the population studied (n = 348,319), 34% were prescribed opioids, 79.5% were white, 36.9% were dually eligible (for both Medicare and Medicaid), 13% lived in a rural area, 52.7% had ≥1 comorbidity, and 16% had a smoking-related diagnosis. Patients exposed to opioids had a lower odds ratio (OR) associated with breast cancer (adjusted OR, 0.96; 95% CI, 0.92-0.99) and colon cancer (adjusted OR, 0.90; 95% CI, 0.86-0.93) compared with controls. Higher ORs for kidney cancer, leukemia, liver cancer, lung cancer, and lymphoma, ranging from lung cancer (OR, 1.04; 95% CI, 1.01-1.07) to liver cancer (OR, 1.19; 95% CI, 1.08-1.31), were present in the exposed population. CONCLUSIONS The current results suggest that an association exists between prescription opioids and incident cancer and that cancer site may play an important role. These findings can direct future research on specific patient populations that may benefit or be harmed by prescription opioid exposure.
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Affiliation(s)
- Jeana E Havidich
- Department of Anesthesiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Julie E Weiss
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.,Norris Cotton Cancer Center, Lebanon, New Hampshire
| | - Tracy L Onega
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.,Norris Cotton Cancer Center, Lebanon, New Hampshire.,The Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine at Dartmouth and the Norris Cotton Cancer Center, Lebanon, New Hampshire.,Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Ying H Low
- Department of Anesthesiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Martha E Goodrich
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.,Norris Cotton Cancer Center, Lebanon, New Hampshire
| | - Mathew A Davis
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.,Department of Systems, Populations, and Leadership, University of Michigan School of Medicine and School of Nursing, Ann Arbor, Michigan
| | - Brian D Sites
- Department of Anesthesiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
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30
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Intraoperative opioids are associated with improved recurrence-free survival in triple-negative breast cancer. Br J Anaesth 2020; 126:367-376. [PMID: 33220939 DOI: 10.1016/j.bja.2020.10.021] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/12/2020] [Accepted: 10/15/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC. METHODS Consecutive patients with stage I-III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data. RESULTS A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88-0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89-1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells. CONCLUSIONS We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue.
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31
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Steele GL, Dudek AZ, Gilmore GE, Richter SA, Olson DA, Eklund JP, Zylla DM. Impact of Pain, Opioids, and the Mu-opioid Receptor on Progression and Survival in Patients With Newly Diagnosed Stage IV Pancreatic Cancer. Am J Clin Oncol 2020; 43:591-597. [PMID: 32482952 DOI: 10.1097/coc.0000000000000714] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Pancreatic adenocarcinoma is frequently associated with pain requiring opioid therapy. Opioids, however, have been implicated in causing tumor progression, ultimately shortening survival. We examined the impact of pain, opioid use, and the mu-opioid receptor (MOP-R) expression in tumor tissue on progression-free survival and overall survival of patients with metastatic pancreatic cancer. METHODS We identified 103 patients with metastatic pancreatic adenocarcinoma receiving chemotherapy and abstracted data from Tumor Registry, in addition to pain, opioid exposure, carbohydrate antigen 19-9 values, survival, and imaging response. MOP-R expression was evaluated using an immunohistochemistry assay. The association of variables with progression-free survival and overall survival was analyzed in univariate and multivariate models. RESULTS Patients with low opioid use (<5 mg oral morphine equivalent/d) survived longer than patients with high opioid (HO) use (≥5 mg oral morphine equivalent/d) (median overall survival of 315 vs. 150 d; hazard ratio [HR]=1.79; 95% confidence interval [CI]: 1.13, 2.84). This effect persisted on multivariate models (adjusted HR=2.76; 95% CI: 1.39, 5.48). Low opioid patients tended to respond better to treatment than HO patients, based on carbohydrate antigen 19-9. Patients with low MOP-R expression had longer median survival (230 vs. 193 d), though the HR was not significant (1.15; 95% CI: 0.71, 1.88). Baseline pain was not associated with outcomes. CONCLUSION In patients with metastatic pancreatic adenocarcinoma, HO use is associated with decreased survival, but the severity of baseline pain and MOP-R expression score in tumor tissue does not correlate with clinical outcomes.
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Affiliation(s)
| | | | | | - Sara A Richter
- Cancer Research Center, HealthPartners/Park Nicollet.,Professional Data Analysts Inc., Minneapolis
| | - Douglas A Olson
- Clinical and Laboratory Medicine, HealthPartners Medical Group & Regions Hospital, Saint Paul, MN
| | | | - Dylan M Zylla
- Cancer Research Center, HealthPartners/Park Nicollet
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32
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Opioid receptors beyond pain control: The role in cancer pathology and the debated importance of their pharmacological modulation. Pharmacol Res 2020; 159:104938. [DOI: 10.1016/j.phrs.2020.104938] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 03/24/2020] [Accepted: 05/15/2020] [Indexed: 12/15/2022]
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Fan X, Wang D, Chen X, Wang R. Effects of Anesthesia on Postoperative Recurrence and Metastasis of Malignant Tumors. Cancer Manag Res 2020; 12:7619-7633. [PMID: 32922072 PMCID: PMC7457832 DOI: 10.2147/cmar.s265529] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/04/2020] [Indexed: 01/17/2023] Open
Abstract
It is difficult to control the recurrence and metastasis of malignant tumors; furthermore, anesthesia is considered one of the main influencing factors. There has been increasing clinical attention on the effects of anesthetic drugs and methods on postoperative tumor growth and metastasis. We reviewed the effects of anesthesia on tumor recurrence and metastasis; specifically, the effects of anesthetic agents, anesthesia methods, and related factors during the perioperative period on the tumor growth and metastasis were analyzed. This study can provide reference standards for rational anesthesia formulations and cancer-related pain analgesia protocols for surgical procedures in patients with malignant tumors. Moreover, it contributes toward an experimental basis for the improvement and development of novel anesthetic agents and methods.
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Affiliation(s)
- Xiaoqing Fan
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, Anhui 230001, People's Republic of China.,Department of Anesthesiology, Anhui Provincial Hospital, Hefei 230001, Anhui, People's Republic of China
| | - Delong Wang
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, Anhui 230001, People's Republic of China.,Department of Anesthesiology, Anhui Provincial Hospital, Hefei 230001, Anhui, People's Republic of China
| | - Xueran Chen
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, People's Republic of China.,Department of Molecular Pathology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui 230031, People's Republic of China
| | - Ruiting Wang
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, Anhui 230001, People's Republic of China.,Department of Anesthesiology, Anhui Provincial Hospital, Hefei 230001, Anhui, People's Republic of China
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Zielińska M, Szymaszkiewicz A, Jacenik D, Schodel L, Sałaga M, Zatorski H, Kordek R, Becker C, Krajewska WM, Fichna J. Cyclic derivative of morphiceptin Dmt-cyclo-(D-Lys-Phe-D-Pro-Asp)-NH2(P-317), a mixed agonist of MOP and KOP opioid receptors, exerts anti-inflammatory and anti-tumor activity in colitis and colitis-associated colorectal cancer in mice. Eur J Pharmacol 2020; 885:173463. [PMID: 32835668 DOI: 10.1016/j.ejphar.2020.173463] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/31/2020] [Accepted: 08/03/2020] [Indexed: 12/07/2022]
Abstract
Endogenous opioid system is involved in the maintenance of the intestinal homeostasis. Recently, we proved that stimulation of opioid receptors using P-317, a cyclic morphiceptin analog, resulted in the alleviation of acute colitis in mice. The aim of the current study was to assess the effect of P-317 during colitis and colitis-associated colorectal cancer in mice. Colitis was induced by addition of dextran sodium sulfate (DSS) into drinking water. Colitis-associated colorectal cancer was induced by a single intraperitoneal injection of azoxymethane (AOM) and subsequent addition of DSS into drinking water (week 2, 5, 8). During macroscopic damage evaluation the samples were collected and used for biochemical (MPO activity assay), molecular (qPCR and western blot) and histological studies. In experimental colitis, P-317 induced an anti-inflammatory response as indicated by macroscopic and microscopic scores. In the colitis-associated colorectal cancer model, a significant difference in colorectal tumor development was observed between vehicle- and P-317-treated mice. P-317 decreased the total number of colonic tumors and inhibited MPO activity. Hematoxylin and eosin staining confirmed anti-tumor activity of P-317. The expression of TNF-α was decreased in P-317-treated mice as compared to the vehicle-treated group. P-317 decreased proliferation as well as β-catenin expression in tumors. P-317, a mixed MOP and KOP receptor agonist, induced an anti-inflammatory response in experimental colitis and decreased tumor development in colitis-associated colorectal cancer in mice.
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Affiliation(s)
- Marta Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Agata Szymaszkiewicz
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Poland
| | - Lena Schodel
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Maciej Sałaga
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Hubert Zatorski
- Department of Pathology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of Digestive Diseases, Medical Univeristy of Lodz, Lodz, Poland
| | - Radzisław Kordek
- Department of Pathology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Christoph Becker
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Wanda M Krajewska
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
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Pallavi B, Sharma P, Baig N, Kumar Madduluri V, Sah AK, Saumya U, Dubey US, Shukla P. Quinoline Glycoconjugates as Potentially Anticancer and Anti‐Inflammatory Agents: An Investigation Involving Synthesis, Biological Screening, and Docking. ChemistrySelect 2020. [DOI: 10.1002/slct.202002345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Badvel Pallavi
- Department of ChemistryBirla Institute of Technology and Science Pilani, Pilani Campus Rajasthan 333031 India
| | - Prachi Sharma
- Department of ChemistryBirla Institute of Technology and Science Pilani, Pilani Campus Rajasthan 333031 India
| | - Noorullah Baig
- Department of ChemistryBirla Institute of Technology and Science Pilani, Pilani Campus Rajasthan 333031 India
| | - Vimal Kumar Madduluri
- Department of ChemistryBirla Institute of Technology and Science Pilani, Pilani Campus Rajasthan 333031 India
| | - Ajay K. Sah
- Department of ChemistryBirla Institute of Technology and Science Pilani, Pilani Campus Rajasthan 333031 India
| | - Udit Saumya
- Department of Biological SciencesBirla Institute of Technology and Science Pilani, Pilani Campus Rajasthan 333031 India
| | - Uma S. Dubey
- Department of Biological SciencesBirla Institute of Technology and Science Pilani, Pilani Campus Rajasthan 333031 India
| | - Paritosh Shukla
- Department of ChemistryBirla Institute of Technology and Science Pilani, Pilani Campus Rajasthan 333031 India
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Ponferrada AR, Orriach JLG, Manso AM, Haro ES, Molina SR, Heredia AF, Lopez MB, Mañas JC. Anaesthesia and cancer: can anaesthetic drugs modify gene expression? Ecancermedicalscience 2020; 14:1080. [PMID: 32863874 PMCID: PMC7434501 DOI: 10.3332/ecancer.2020.1080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Indexed: 01/21/2023] Open
Abstract
Cancer remains a primary cause of morbidity and mortality worldwide, and its incidence continues to increase. The most common cause of death in cancer patients is tumour recurrence. Surgery is the gold standard in the treatment of most tumours. However, cancer surgery can lead to the release of tumour cells into the systemic circulation. Surgical stress and several perioperative factors have been suggested to boost tumour growth, thereby increasing the risk of metastatic recurrence. Preclinical and clinical studies suggest that anaesthetics and adjuvants administered during the perioperative period may impact cancer recurrence and survival. This document summarises the current evidence regarding the effects of anaesthetic drugs and analgesic techniques on the immune system, systemic inflammatory response and tumour cells, as well as their impact on cancer recurrence.
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Affiliation(s)
- Aida Raigon Ponferrada
- Institute of Biomedical Research in Malaga [IBIMA], Malaga 29010, Spain
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga 29010, Spain
| | - Jose Luis Guerrero Orriach
- Institute of Biomedical Research in Malaga [IBIMA], Malaga 29010, Spain
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga 29010, Spain
- Department of Pharmacology and Pediatrics, School of Medicine, University of Malaga, Malaga 29010, Spain
- Member of COST Action 15204
| | - Alfredo Malo Manso
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga 29010, Spain
| | - Enrique Sepúlveda Haro
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga 29010, Spain
| | - Salvador Romero Molina
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga 29010, Spain
| | - Ana Fontaneda Heredia
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga 29010, Spain
| | - Manolo Baena Lopez
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga 29010, Spain
| | - Jose Cruz Mañas
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga 29010, Spain
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Chen J, Xia J, Huang J, Xu R. Effect of aspirin on PET parameters in primary non-small cell lung cancer and its relationship with prognosis. BMC Cancer 2020; 20:510. [PMID: 32493238 PMCID: PMC7268630 DOI: 10.1186/s12885-020-06983-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 05/20/2020] [Indexed: 11/19/2022] Open
Abstract
Background 18 F-FDG is a glucose analogue whose metabolic index SUV can effectively reflect the metabolic level of tumor microenvironment. Aspirin can affect the uptake of 18F-FDG by cancer cells, reducing the SUVmax value of primary tumors, exerting antitumor effect. This study aimed to evaluate the prognostic value of long-term aspirin and the relationship between aspirin intake and PET parameters value of primary tumor in non-small cell lung cancer (NSCLC). Methods Eighty-one NSCLC patients were recruited and divided into two groups: aspirin medication group and control group, who underwent surgery and had pathological diagnosis data between January 2012 and December 2016. Clinical characteristics were retrospective analyzed to evaluate the possibility of clinical prognosis, respectively. Kaplan-Meier curves and a Cox proportional hazard model were applied to evaluate the predictors of prognosis. Results The PET/CT SUVmax of the primary tumor in the aspirin group was lower than that in the control group (P < 0.05). Compared with the control group, the SUVmax, SUVmean and TLG of the primary tumor in aspirin group were lower, but the MTV value had no significant difference. Cox regression analysis showed that N stage and TNM stage were predictors of the prognosis. There was a significant difference in the use of aspirin in NSCLC patients. Conclusion Aspirin can reduce SUVmax, SUVmean and TLG in primary tumor and aspirin can improve the prognosis of patients with NSCLC.
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Affiliation(s)
- Jinghua Chen
- First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, P. R. China.,Second Clinical Medicine College, Jinan University, Shenzhen, 518020, P. R. China.,Department of Medical Oncology, Shenzhen People's Hospital, Shenzhen, 518020, P. R. China
| | - Junxian Xia
- First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, P. R. China.,Second Clinical Medicine College, Jinan University, Shenzhen, 518020, P. R. China.,Department of Medical Oncology, Shenzhen People's Hospital, Shenzhen, 518020, P. R. China
| | - Jiacheng Huang
- First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, P. R. China.,Second Clinical Medicine College, Jinan University, Shenzhen, 518020, P. R. China.,Department of Medical Oncology, Shenzhen People's Hospital, Shenzhen, 518020, P. R. China
| | - Ruilian Xu
- First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, P. R. China. .,Second Clinical Medicine College, Jinan University, Shenzhen, 518020, P. R. China. .,Department of Medical Oncology, Shenzhen People's Hospital, Shenzhen, 518020, P. R. China.
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Wang RD, Zhu JY, Zhu Y, Ge YS, Xu GL, Jia WD. Perioperative analgesia with parecoxib sodium improves postoperative pain and immune function in patients undergoing hepatectomy for hepatocellular carcinoma. J Eval Clin Pract 2020; 26:992-1000. [PMID: 31407484 DOI: 10.1111/jep.13256] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 07/13/2019] [Accepted: 07/27/2019] [Indexed: 11/29/2022]
Abstract
RATIONALE, AIMS, AND OBJECTIVES Acute postoperative pain can result in immune dysfunction, which can be partly mitigated by efficient pain management. Opioids that have been widely applied to analgesia have been shown to suppress immune function, which has a negative impact on the treatment of patients with cancer. This study investigated the effects of perioperative fentanyl analgesia alone or in combination with parecoxib sodium on postoperative pain, immune function, and prognosis in patients undergoing hepatectomy of hepatocellular carcinoma (HCC). METHODS A total of 80 patients scheduled for hepatectomy between October 2013 and August 2014 were included. Patients were randomly divided into two groups (n = 40) and allocated to receive parecoxibsodium 40 mg (group P) or placebo (group C) 30 minutes before induction of anaesthesia, followed by 40 mg every 12 hours for 48 hours after the operation. All patients had access to patient-controlled analgesia with intravenous fentanylpostoperatively. Venous blood samples were collected at the following time points: 30 minutes before induction of anaesthesia (T0), the end of the surgery (T1), 24 hours after surgery (T2), and 72 hours after surgery (T3). The percentages of CD3+, CD4+, CD8+, CD4+/CD8+ T cells, and CD3+CD16+CD56+ (NK) cells at these time points were quantified by flow cytometry (FCM).Visual analogue scale (VAS) scores, total fentanyl consumption, and adverse effects were recorded. The prognostic differences in overall survival (OS) and disease-free survival (DFS) between the two groups was also investigated. RESULTS For both groups, the percentages of CD3+, CD4+ T cells, and the ratio of CD4+/CD8+ significantly decreased at T1 and T2 (P < .05). The percentages of CD3+ T cells were significantly lower in group C than that in group P at T2 (P < .05). In group C, the amount of CD3+ T cells was lower at T3 compared with T0 (P < .05). The percentages of NK cells significantly decreased at T1 in both groups (P < .05). The percentages of NK in group P were recovered nearly to baseline (T0) at T2, which was higher than that of group C (P < .05). In group C, the percentages of NK cells have not recovered nearly to baseline at T3 compared with T0 (P < .05). VAS scores at rest and on cough in group P were significantly lower than those in group C at 2, 6, 12, and 24 hours after operation (P < .05), and there were no significant differences in VAS scores between the two groups at 48 hours after surgery (P > .05). There were no significant differences regarding the incidence of adverse effects between the two groups (P > .05). Kaplan-Meier analysis indicated that the DFS time in group P was significantly longer than in group C (19.0 months, 95% confidence interval [CI], 9.8-28.2 vs 14.0 months, 95% CI, 8.1-19.9; P < .05). There was no significant difference in OS time (36.0 months, 95% CI, 13.4-58.9 vs 14.0 months, 95% CI, 10.6-25.4; P > .05) between two groups. CONCLUSIONS The present study indicated that perioperative analgesia of parecoxib sodium combined with patient-controlled analgesic fentanyl resulted in better preserved immune function with enhancement of the analgesic efficacy to fentanyl alone of HCC patients undergoing hepatectomy and helped postpone postoperative tumour recurrence.
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Affiliation(s)
- Run-Dong Wang
- Department of Hepatic Surgery, The First Affiliated Hospital of USTC, Hefei, China
| | - Jian-Yu Zhu
- Department of Trauma Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yu Zhu
- Department of Hepatic Surgery, The First Affiliated Hospital of USTC, Hefei, China.,School of Medicine, Shandong University, Jinan, China.,Taizhou Hospital, Wenzhou Medical University, Taizhou, China
| | - Yong-Sheng Ge
- Department of Hepatic Surgery, The First Affiliated Hospital of USTC, Hefei, China
| | - Ge-Liang Xu
- Department of Hepatic Surgery, The First Affiliated Hospital of USTC, Hefei, China
| | - Wei-Dong Jia
- Department of Hepatic Surgery, The First Affiliated Hospital of USTC, Hefei, China
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Liu Z, Cheng S, Fu G, Ji F, Wang C, Cao M. Postoperative administration of ketorolac averts morphine-induced angiogenesis and metastasis in triple-negative breast cancer. Life Sci 2020; 251:117604. [PMID: 32243929 DOI: 10.1016/j.lfs.2020.117604] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 03/15/2020] [Accepted: 03/24/2020] [Indexed: 01/07/2023]
Abstract
AIMS Opioids (i.e. morphine) were found to induce triple negative breast cancer (TNBC) metastasis while nonsteroidal anti-inflammatory drugs (i.e. ketolorac) were associated with decreased metastasis in TNBC. These contradictory findings demand clarification on the effect of postoperative morphine and ketorolac on TNBC metastasis. MATERIALS AND METHODS TNBC xenograft mice were established using MDA-MB-231 cells. When tumors reached ~100 mm3, the primary tumor was resected. Mice were then randomly assigned to four groups (n = 14): (i) saline, (ii) morphine (10 mg kg-1) (iii) morphine + ketorolac (10 mg kg-1 of morphine and 20 mg kg-1 of ketorolac) (iv) ketorolac (20 mg kg-1); administrated for three consecutive days after resection. Three weeks after resection, the number of lung metastases was measured. Microvessel density, thrombospondin-1 (TSP-1) and c-Myc expression in recurrent tumors were determined. To elucidate the above phenomenon in vitro, MDA-MB-231 cells were treated according to the regiment above; with or without supplementation of an AKT inhibitor to determine the activation of PI3K/AKT/c-Myc pathway. KEY FINDINGS In mice, morphine promoted TNBC metastasis and angiogenesis, decreased TSP-1 expression and increased c-Myc expression, while co-administration of ketorolac significantly reversed the phenotypes above (p < .05). Mechanistically, morphine inhibited TSP-1 secretion by activating PI3K/AKT/c-Myc pathway (p < .05), while ketorolac promoted TSP-1 secretion (p < .05) by suppressing PI3K/AKT/c-Myc pathway. SIGNIFICANCE Our study indicated that morphine enhanced TNBC metastasis and angiogenesis while ketorolac suppressed this effect. Mechanistically, this may be related to the enhancement of TSP-1 synthesis after ketorolac administration which further de-activated PI3K/AKT/c-Myc pathway.
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Affiliation(s)
- Zhongqi Liu
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Shi Cheng
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Ganglan Fu
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Fengtao Ji
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Chengli Wang
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Minghui Cao
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
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Abstract
OPINION STATEMENT Opioids are the gold standard for the treatment of cancer-related pain. Preclinical studies have associated opioids with cancer progression and overall survival. In mice models, opioids have been shown to possess pro-tumor activity secondary to immunosuppression, migration of tumor cells, increased activity of vascular endothelial growth factor receptors, and angiogenesis leading to tumor progression. In contrast, opioids have also been associated with having antitumor activity by activation of apoptosis and phagocytosis. However, high-quality randomized controlled trials in humans that are focused on the association between opioids and survival in cancer patients are lacking, which underscores the importance of being cautious when interpreting the results of the preclinical studies. Cancer-related pain is complex and multifactorial and may worsen as the disease progresses leading to higher opioid utilization. Moreover, cancer pain by itself has been associated with poor survival. The survival in these advanced cancer patients taking opioids may be more likely to be associated with cancer progression and not the opioid use. Adequate treatment of cancer pain has the potential to improve quality of life and performance status, highlighting the importance of continuing to use opioids to manage pain efficiently. More research is clearly needed.
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Lee YJ, Oh CS, Choi JM, Park S, Kim SH. mu-Opioid Receptor Polymorphisms and Breast Cancer Recurrence in Adult Korean Women Undergoing Breast Cancer Surgery: A Retrospective Study. Int J Med Sci 2020; 17:2941-2946. [PMID: 33173414 PMCID: PMC7646095 DOI: 10.7150/ijms.49297] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 10/07/2020] [Indexed: 01/18/2023] Open
Abstract
Background: Genetic variations of mu-opioid receptors are well known to contribute to growth and progression of tumors. The most common single-nucleotide polymorphism (SNP) in the mu-opioid receptor 1 gene (OPRM1) is the A118G mutation. We examined the association between the recurrent breast cancer and genotypes of OPRM1 A118G SNP (AA vs. AG vs. GG) in Korean women population. Methods: We analysed medical records and genetic data of 200 patients aged more than 20 who underwent primary breast cancer surgery from June 2012 to June 2014 and diagnosed recurrent breast cancer from June 2012 to September 2019. Results: The incidence of recurrent breast cancer was 6.1%, 8.2%, and 4.8% in genotype AA, AG and GG, respectively (p=0.780). The incidence of recurrent breast cancer in volatile anaesthesia group was 7.0% and 7.1% in total intravenous anaesthesia (TIVA) group (RR = 0.984, 95% CI = 0.328 - 2.951; p = 0.978). Conclusion: OPRM1 A118G SNP had no influence on breast cancer recurrence in Korean women. Anaesthesia technique did not show significant effect on the incidence of recurrent breast cancer.
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Affiliation(s)
- Yea-Ji Lee
- Department of Anaesthesiology and Pain medicine, Konkuk University Medical Centre, Konkuk University School of Medicine, Seoul, Korea
| | - Chung-Sik Oh
- Department of Anaesthesiology and Pain medicine, Konkuk University Medical Centre, Konkuk University School of Medicine, Seoul, Korea.,Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
| | - Ji Min Choi
- Department of Anaesthesiology and Pain medicine, Konkuk University Medical Centre, Konkuk University School of Medicine, Seoul, Korea
| | - Sangtae Park
- Department of Anaesthesiology and Pain medicine, Konkuk University Medical Centre, Konkuk University School of Medicine, Seoul, Korea
| | - Seong-Hyop Kim
- Department of Anaesthesiology and Pain medicine, Konkuk University Medical Centre, Konkuk University School of Medicine, Seoul, Korea.,Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea.,Department of Infection and Immunology, Konkuk University School of Medicine, Seoul, Korea
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Tramadol use is associated with enhanced postoperative outcomes in breast cancer patients: a retrospective clinical study with in vitro confirmation. Br J Anaesth 2019; 123:865-876. [DOI: 10.1016/j.bja.2019.09.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/17/2022] Open
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Perry JA, Douglas H. Immunomodulatory Effects of Surgery, Pain, and Opioids in Cancer Patients. Vet Clin North Am Small Anim Pract 2019; 49:981-991. [PMID: 31581985 DOI: 10.1016/j.cvsm.2019.07.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Surgery is the mainstay of therapy for canine and human solid cancers. Alarmingly, evidence suggests that the process of surgery may exacerbate metastasis and accelerate the kinetics of cancer progression. Understanding the mechanisms by which cancer progression is accelerated as a result of surgery may provide pharmacologic interventions. This review discusses surgery-induced cancer progression. It focuses on immunomodulatory properties of anesthesia and opioids and evidence that studies evaluating the role of opioids in tumor progression are indicated. It concludes by discussing why companion animals with spontaneously arising cancer are an ideal model for clinical trials to investigate this phenomenon.
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Affiliation(s)
- James A Perry
- Veterinary Cancer and Surgery Specialists, 10400 Southeast Main Street, Milwaukie, OR 97222, USA.
| | - Hope Douglas
- University of Pennsylvania, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, 3900 Delancey Street, Philadelphia, PA 19104, USA
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Schoos A, Gabriel C, Knab VM, Fux DA. Activation of HIF-1 α by δ-Opioid Receptors Induces COX-2 Expression in Breast Cancer Cells and Leads to Paracrine Activation of Vascular Endothelial Cells. J Pharmacol Exp Ther 2019; 370:480-489. [PMID: 31300611 DOI: 10.1124/jpet.119.257501] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 06/24/2019] [Indexed: 01/05/2023] Open
Abstract
Opioids promote tumor angiogenesis in mammary malignancies, but the underlying signaling mechanism is largely unknown. The current study investigated the hypothesis that stimulation of δ-opioid receptors (DOR) in breast cancer (BCa) cells activates the hypoxia-inducible factor 1α (HIF-1α), which triggers synthesis and release of diverse angiogenic factors. Immunoblotting revealed that incubation of human MCF-7 and T47D breast cancer cells with the DOR agonist d-Ala2,d-Leu5-enkephalin (DADLE) resulted in a transient accumulation and thus activation of HIF-1α DADLE-induced HIF-1α activation preceded PI3K/Akt stimulation and was blocked by the DOR antagonist naltrindole and naloxone, pertussis toxin, different phosphoinositide 3-kinase (PI3K) inhibitors, and the Akt inhibitor Akti-1/2. Whereas DADLE exposure had no effect on the expression and secretion of vascular endothelial growth factor (VEGF) in BCa cells, an increased abundance of cyclooxygenase-2 (COX-2) and release of prostaglandin E2 (PGE2) was detected. DADLE-induced COX-2 expression was also observed in three-dimensional cultured MCF-7 cells and impaired by PI3K/Akt inhibitors and the HIF-1α inhibitor echinomycin. Supernatant from DADLE-treated MCF-7 cells triggered sprouting of endothelial (END) cells, which was blocked when MCF-7 cells were pretreated with echinomycin or the COX-2 inhibitor celecoxib. Also no sprouting was observed when END cells were exposed to the PGE2 receptor antagonist PF-04418948. The findings together indicate that DOR stimulation in BCa cells leads to PI3K/Akt-dependent HIF-1α activation and COX-2 expression, which trigger END cell sprouting by paracrine activation of PGE2 receptors. These findings provide a potential mechanism of opioid-driven tumor angiogenesis and thus therapeutic targets to combat the tumor-angiogenic opioid effect. SIGNIFICANCE STATEMENT: Opioids are indispensable analgesics for treating cancer-related pain. However, opioids were found to promote tumor growth and metastasis, which questions the use of these potent pain-relieving drugs in cancer patients. Enhanced tumor vascularization after opioid treatment implies that tumor progression results from angiogenic opioid effects. Thus, understanding the signaling mechanism of opioid-driven tumor angiogenesis helps to identify therapeutic targets to combat these undesired tumor effects. The present study reveals that stimulation of δ-opioid receptors in breast cancer cells leads to an activation of HIF-1α and expression of COX-2 via PI3K/Akt stimulation, which results in a paracrine activation of vascular endothelial cells by prostaglandin E2 receptors.
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Affiliation(s)
- Alexandra Schoos
- Division Clinical Pharmacology, Institute of Pharmacology and Toxicology (A.S., V.M.K., D.A.F.) and Institute of Pathology and Forensic Veterinary Medicine (C.G.), University of Veterinary Medicine Vienna, Vienna, Austria
| | - Cordula Gabriel
- Division Clinical Pharmacology, Institute of Pharmacology and Toxicology (A.S., V.M.K., D.A.F.) and Institute of Pathology and Forensic Veterinary Medicine (C.G.), University of Veterinary Medicine Vienna, Vienna, Austria
| | - Vanessa M Knab
- Division Clinical Pharmacology, Institute of Pharmacology and Toxicology (A.S., V.M.K., D.A.F.) and Institute of Pathology and Forensic Veterinary Medicine (C.G.), University of Veterinary Medicine Vienna, Vienna, Austria
| | - Daniela A Fux
- Division Clinical Pharmacology, Institute of Pharmacology and Toxicology (A.S., V.M.K., D.A.F.) and Institute of Pathology and Forensic Veterinary Medicine (C.G.), University of Veterinary Medicine Vienna, Vienna, Austria
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Özgürbüz U, Gencür S, Kurt FÖ, Özkalkanlı M, Vatansever HS. The effects of tramadol on cancer stem cells and metabolic changes in colon carcinoma cells lines. Gene 2019; 718:144030. [PMID: 31390540 DOI: 10.1016/j.gene.2019.144030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 07/29/2019] [Accepted: 07/30/2019] [Indexed: 11/30/2022]
Abstract
Opioids are widely used in the treatment of cancer related pain. They mainly exert their effects on opioid receptors. The most common opioid in the treatment of pain is morphine. Previous studies show that they may have effects on cancer cell behavior. These may include apoptosis, angiogenesis, invasion, inflammation and immune reactions. Tramadol, also an opioid is widely used in the treatment of cancer pain and is not well studied in cancer behavior. We aimed to investigate the effects of tramadol on cancer stem cells and metabolic changes in colon carcinoma cells. We used Colo320 (ATCC, CCL-220), Colo741 (ECACC, 93052621) and HCT116 (ATCC, CCL-247) colon cancer cell lines. CD133 was considered colon cancer stem cell marker and used to sort CD133+ and CD133- cells by magnetic cell sorting. MTT (mitochondria-targeted therapeutics) technique was used to detect tramadol's cytotoxic effect on cells in the study groups. Cells were treated with 1 mg/kg, 1.5 mg/kg and 2 mg/kg tramadol for 24 h at 37 °C and 5% CO2.Caspase-3, Ki-67, Bcl-2 and VGEF distributions were performed using indirect immunoperoxidase staining for immunohistochemical analysis. The study showed that tramadol has triggering effect on apoptosis in Colo320 colon cancer stem cells.
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Affiliation(s)
- Uğur Özgürbüz
- İzmir Atatürk Research and Training Hospital, Dept. of Anesthesiology and Reanimation, Turkey.
| | - Sema Gencür
- Manisa Celal Bayar University, Dept. of Histology and Embryology, Turkey
| | - Feyzan Özdal Kurt
- Manisa Celal Bayar University, Faculty of Science & Letters, Dept. of Biology, Turkey
| | - Murat Özkalkanlı
- İzmir Atatürk Research and Training Hospital, Dept. of Anesthesiology and Reanimation, Turkey
| | - H Seda Vatansever
- Manisa Celal Bayar University, Dept. of Histology and Embryology, Turkey; Near East University, Experimental Research Center of Health (DESAM), Mersin 10, Turkey
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Abstract
Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies. Diverse drugs targeting malignant and nonmalignant cells receive clinical approval each year from the FDA. Targeting cancer cells and nonmalignant cells unavoidably changes the tumor microenvironment, and cellular and molecular components relentlessly alter in response to drugs. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. While cancer cells' dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug responses are less understood. This Review focuses on emerging mechanisms involving adipocytes and lipid metabolism in altering the response to cancer treatment. In particular, we discuss mechanisms underlying cancer-associated adipocytes and lipid metabolic reprogramming in cancer drug resistance.
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Influence of perioperative anaesthetic and analgesic interventions on oncological outcomes: a narrative review. Br J Anaesth 2019; 123:135-150. [PMID: 31255291 DOI: 10.1016/j.bja.2019.04.062] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/18/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
Surgery is an important treatment modality for the majority of solid organ cancers. Unfortunately, cancer recurrence following surgery of curative intent is common, and typically results in refractory disease and patient death. Surgery and other perioperative interventions induce a biological state conducive to the survival and growth of residual cancer cells released from the primary tumour intraoperatively, which may influence the risk of a subsequent metastatic disease. Evidence is accumulating that anaesthetic and analgesic interventions could affect many of these pathophysiological processes, influencing risk of cancer recurrence in either a beneficial or detrimental way. Much of this evidence is from experimental in vitro and in vivo models, with clinical evidence largely limited to retrospective observational studies or post hoc analysis of RCTs originally designed to evaluate non-cancer outcomes. This narrative review summarises the current state of evidence regarding the potential effect of perioperative anaesthetic and analgesic interventions on cancer biology and clinical outcomes. Proving a causal link will require data from prospective RCTs with oncological outcomes as primary endpoints, a number of which will report in the coming years. Until then, there is insufficient evidence to recommend any particular anaesthetic or analgesic technique for patients undergoing tumour resection surgery on the basis that it might alter the risk of recurrence or metastasis.
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Chen D, Pan J, Chen Y, Xing W, Yan Y, Yuan Y, Zeng W. The mu-opioid receptor is a molecular marker for poor prognosis in hepatocellular carcinoma and represents a potential therapeutic target. Br J Anaesth 2019; 122:e157-e167. [DOI: 10.1016/j.bja.2018.09.030] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 09/07/2018] [Accepted: 09/17/2018] [Indexed: 01/17/2023] Open
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Persistent opioid use is associated with worse survival after lobectomy for stage I non-small cell lung cancer. Pain 2019; 160:2365-2373. [DOI: 10.1097/j.pain.0000000000001630] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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