Eizoh Gondoh1,2, Yusuke Hamada2,3, Tomohisa Mori2, Yusuke Iwazawa2, Asami Shinohara2, Michiko Narita3,4, Daisuke Sato2,3, Hiroyuki Tezuka5, Takayasu Yamauchi6, Mayu Tsujimura2, Sara Yoshida2,3, Kenichi Tanaka2,3, Kensuke Yamashita2, Haruka Akatori6, Kimio Higashiyama6, Kazuhiko Arakawa2, Yukari Suda2,3, Kanako Miyano3, Masako Iseki1, Eiichi Inada7, Naoko Kuzumaki8,9, Minoru Narita10,11,12. 1. Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. 2. Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. 3. Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. 4. Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan. 5. Department of Cellular Function Analysis, Research Promotion Headquarters, Fujita Health University, Aichi, Japan. 6. Institute of Medicinal Chemistry, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. 7. Department of Anesthesiology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. 8. Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. n-kuzumaki@hoshi.ac.jp. 9. Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. n-kuzumaki@hoshi.ac.jp. 10. Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. narita@hoshi.ac.jp. 11. Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. narita@hoshi.ac.jp. 12. Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. narita@hoshi.ac.jp.
Abstract
BACKGROUND: It has been considered that activation of peripheral μ-opioid receptors (MORs) induces side effects of opioids. In this study, we investigated the possible improvement of the immune system in tumour-bearing mice by systemic administration of the peripheral MOR antagonist naldemedine. METHODS: The inhibitory effect of naldemedine on MOR-mediated signalling was tested by cAMP inhibition and β-arrestin recruitment assays using cultured cells. We assessed possible changes in tumour progression and the number of splenic lymphocytes in tumour-bearing mice under the repeated oral administration of naldemedine. RESULTS: Treatment with naldemedine produced a dose-dependent inhibition of both the decrease in the cAMP level and the increase in β-arrestin recruitment induced by the MOR agonists. Repeated treatment with naldemedine at a dose that reversed the morphine-induced inhibition of gastrointestinal transport, but not antinociception, significantly decreased tumour volume and prolonged survival in tumour-transplanted mice. Naldemedine administration significantly decreased the increased expression of immune checkpoint-related genes and recovered the decreased level of toll-like receptor 4 in splenic lymphocytes in tumour-bearing mice. CONCLUSIONS: The blockade of peripheral MOR may induce an anti-tumour effect through the recovery of T-cell exhaustion and promotion of the tumour-killing system.
BACKGROUND: It has been considered that activation of peripheral μ-opioid receptors (MORs) induces side effects of opioids. In this study, we investigated the possible improvement of the immune system in tumour-bearing mice by systemic administration of the peripheral MOR antagonist naldemedine. METHODS: The inhibitory effect of naldemedine on MOR-mediated signalling was tested by cAMP inhibition and β-arrestin recruitment assays using cultured cells. We assessed possible changes in tumour progression and the number of splenic lymphocytes in tumour-bearing mice under the repeated oral administration of naldemedine. RESULTS: Treatment with naldemedine produced a dose-dependent inhibition of both the decrease in the cAMP level and the increase in β-arrestin recruitment induced by the MOR agonists. Repeated treatment with naldemedine at a dose that reversed the morphine-induced inhibition of gastrointestinal transport, but not antinociception, significantly decreased tumour volume and prolonged survival in tumour-transplanted mice. Naldemedine administration significantly decreased the increased expression of immune checkpoint-related genes and recovered the decreased level of toll-like receptor 4 in splenic lymphocytes in tumour-bearing mice. CONCLUSIONS: The blockade of peripheral MOR may induce an anti-tumour effect through the recovery of T-cell exhaustion and promotion of the tumour-killing system.
Authors: Dylan Zylla; Brett L Gourley; Derek Vang; Scott Jackson; Sonja Boatman; Bruce Lindgren; Michael A Kuskowski; Chap Le; Kalpna Gupta; Pankaj Gupta Journal: Cancer Date: 2013-09-16 Impact factor: 6.860
Authors: Gregory Corder; Vivianne L Tawfik; Dong Wang; Elizabeth I Sypek; Sarah A Low; Jasmine R Dickinson; Chaudy Sotoudeh; J David Clark; Ben A Barres; Christopher J Bohlen; Grégory Scherrer Journal: Nat Med Date: 2017-01-16 Impact factor: 53.440