期刊
BRITISH JOURNAL OF CANCER
卷 127, 期 8, 页码 1565-1574出版社
SPRINGERNATURE
DOI: 10.1038/s41416-022-01928-x
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资金
- MEXT-Supported Program for the Strategic Research Foundation at Private Universities [S1411019]
- Hoshi University
This study found that systemic administration of the peripheral mu-opioid receptor (MOR) antagonist naldemedine improved the immune system in tumour-bearing mice, reducing tumour volume and prolonging survival. The blockade of peripheral MORs may lead to anti-tumour effects by recovering T-cell exhaustion and promoting the tumour-killing system.
BACKGROUND: It has been considered that activation of peripheral mu-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 beta-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 beta-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.
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