Arsenic trioxide inhibits lung metastasis of mouse colon cancer via reducing the infiltration of regulatory T cells.
The purpose of this study was to investigate the effects of arsenic trioxide (As2O3) on the infiltration of regulatory T cells (Tregs) in the local lung metastasis of mouse colon cancer in vivo and the regulation of Tregs in cytokine-induced killer cells (CIKs) in vitro. A high Tregs infiltration mouse colon cancer lung metastasis model was established by intravenous injection of CT26 murine colon carcinoma cells. Tumor-bearing mice were randomly divided into three groups: control group, low-dose As2O3group, and high-dose As2O3group. For in vitro studies, CIKs were treated with vehicle control or 0.1, 1, or 5 μM As2O3. The level of Tregs was detected via flow cytometry, Foxp3 expression was assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR), the level of interferon gamma (IFN-γ) was evaluated by enzyme-linked immunoassay (ELISA), and the cytotoxic activity of As2O3-treated CIKs was assessed through a lactate dehydrogenase (LDH) release assay. Obvious lung metastasis was observed 3 days after CT26 murine colon carcinoma cell injection. The numbers of Tregs in the lungs and spleens of tumor-bearing mice were significantly higher than those of the normal group (p < 0.01). As2O3treatment increased the mouse weight as well as reduced the number of metastatic lung nodules and the lung/body weight ratio (p < 0.01). Moreover, As2O3treatment significantly reduced the Tregs proportion and the Foxp3 messenger RNA (mRNA) levels in metastatic lung tissues (p < 0.01). In vitro, As2O3significantly reduced the Tregs proportion and the Foxp3 mRNA levels (p < 0.01) and significantly increased the cytotoxic activity of CIKs and the IFN-γ levels in the supernatant of cultured CIKs (p < 0.01). As2O3might inhibit lung metastasis of colon cancer by reducing the local infiltration of Tregs and increase the cytotoxic activity of CIKs by suppressing Tregs.
Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.|Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Disease of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantatation, Wuhan, 430071, China.
Lei
L
Wang
Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
Xiang
X
Hu
Institute of General Surgery, Chinese PLA General Hospital, Beijing, 100853, China. xyx20151026@sina.com.
Yingxin
Y
Xu
Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China. surgerydoctor@sina.com.|Department of General Surgery, First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China. surgerydoctor@sina.com.
Zhong
Z
Liu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D055612:Cytokine-Induced Killer Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D010087:Oxides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001152:Arsenicals; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D010087:Oxides; D012333:RNA, Messenger; D000077237:Arsenic Trioxide
Arsenic trioxide; Colon cancer; Cytokine-induced killer cells; Lung metastasis; Regulatory T cells
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