PMID- 38041778
OWN - NLM
STAT- Publisher
LR  - 20231202
IS  - 1432-1912 (Electronic)
IS  - 0028-1298 (Linking)
DP  - 2023 Dec 2
TI  - Tramadol suppresses growth of orthotopic liver tumors via promoting M1 macrophage 
      polarization in the tumor microenvironment.
LID - 10.1007/s00210-023-02871-1 [doi]
AB  - Tumor-associated macrophages (TAMs) are major infiltrating immune cells in liver 
      cancer. They are polarized to anti-tumor M1 type or tumor-supporting M2 type in a 
      dynamic changing state. Tramadol, a synthetic opioid, exhibits tumor-suppressing 
      effect in several cancers, but whether it plays a role in TAMs polarization is 
      uncertain. In the present study, the potential influence of tramadol on TAMs 
      polarization was explored in liver cancer. An orthotopic murine Hepa 1-6 liver 
      cancer model was constructed. The potential function of tramadol was evaluated by 
      cell viability assay, EdU incorporation assay, flow cytometry, 
      immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), 
      enzyme-linked immunosorbent assay (ELISA) assay, T cell proliferation and 
      suppression assays and western blot. We found that tramadol suppressed 
      proliferation and tumor formation of murine Hepa 1-6 cells in vitro and in vivo. 
      Tramadol reprogramed the immune microenvironment to favor M1 macrophage 
      polarization in orthotopic Hepa 1-6 tumors. Moreover, tramadol facilitated M1 
      macrophage polarization and inhibited M2 macrophage polarization of bone 
      marrow-derived macrophages (BMDMs) and human THP-1 macrophages in vitro. 
      Furthermore, tramadol-treated BMDMs promoted proliferation and activation of 
      splenic CD4(+) and CD8(+) T cells. Tramadol induced cellular ROS production and 
      mitochondrial dysfunction of BMDMs. Finally, tramadol activated NF-kappaB signaling 
      in BMDMs and THP-1 macrophages, while inhibition of NF-kappaB signaling by JSH-23 
      attenuated the influence of tramadol on macrophage polarization. In conclusion, 
      these data elucidated a novel anti-tumor mechanism of tramadol in liver cancer. 
      Tramadol might be a promising treatment strategy for liver cancer patients.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, 
      part of Springer Nature.
FAU - Wang, Lei
AU  - Wang L
AD  - Department of Anesthesiology, the First Affiliated Hospital of Dalian Medical 
      University., No. 222 Zhongshan Road, Xigang District, Dalian, 116000, China.
FAU - Guo, Weijia
AU  - Guo W
AD  - Department of Anesthesiology, the First Affiliated Hospital of Dalian Medical 
      University., No. 222 Zhongshan Road, Xigang District, Dalian, 116000, China.
FAU - Guan, Hongman
AU  - Guan H
AD  - Department of Anesthesiology, the First Affiliated Hospital of Dalian Medical 
      University., No. 222 Zhongshan Road, Xigang District, Dalian, 116000, China.
FAU - Yan, Ni
AU  - Yan N
AD  - Department of Anesthesiology, the First Affiliated Hospital of Dalian Medical 
      University., No. 222 Zhongshan Road, Xigang District, Dalian, 116000, China.
FAU - Cai, Xiaolan
AU  - Cai X
AD  - Department of Anesthesiology, the First Affiliated Hospital of Dalian Medical 
      University., No. 222 Zhongshan Road, Xigang District, Dalian, 116000, China.
FAU - Zhu, Lili
AU  - Zhu L
AD  - Department of Gynaecology and Obstetrics, the First Affiliated Hospital of Dalian 
      Medical University. , No. 222 Zhongshan Road, Xigang District, Dalian, 116000, 
      China. zhulili20230@163.com.
LA  - eng
PT  - Journal Article
DEP - 20231202
PL  - Germany
TA  - Naunyn Schmiedebergs Arch Pharmacol
JT  - Naunyn-Schmiedeberg's archives of pharmacology
JID - 0326264
SB  - IM
OTO - NOTNLM
OT  - Liver cancer
OT  - Macrophage polarization
OT  - NF-kappaB
OT  - Tramadol
OT  - Tumor-associated macrophages
EDAT- 2023/12/02 12:42
MHDA- 2023/12/02 12:42
CRDT- 2023/12/02 11:15
PHST- 2023/07/04 00:00 [received]
PHST- 2023/11/21 00:00 [accepted]
PHST- 2023/12/02 12:42 [medline]
PHST- 2023/12/02 12:42 [pubmed]
PHST- 2023/12/02 11:15 [entrez]
AID - 10.1007/s00210-023-02871-1 [pii]
AID - 10.1007/s00210-023-02871-1 [doi]
PST - aheadofprint
SO  - Naunyn Schmiedebergs Arch Pharmacol. 2023 Dec 2. doi: 10.1007/s00210-023-02871-1.