Abstract
Capecitabine (CAP) is now widely used in the comprehensive treatment of digestive system tumors. Some clinical observations have shown that CAP may have immunosuppressive effects, but there is still a lack of clear experimental verification. In this study, different doses of CAP were administered to normal mice by gavage. Our results confirmed that CAP did not cause myelosuppression in bone marrow tissue; CAP selectively reduced the proportion of T cells and the concentration of related pro-inflammatory cytokines, while it increased the concentration of anti-inflammatory cytokines. Thymidylate phosphorylase (TP) is the key enzyme for the transformation of CAP in vivo; this study confirmed that T cells express TP, but the bone marrow tissue lacks TP expression, which explains the selectivity in pharmacodynamic effects of CAP. In addition, it was confirmed that CAP can induce T cell apoptosis in vivo and in vitro. In vitro experiments showed that CAP-induced T cell apoptosis was related to TP expression, endoplasmic reticulum stress (ERS) induction, reactive oxygen species (ROS) production, and mitochondria-mediated apoptosis activation. Therefore, this study confirmed that the differential expression of TP in cells and tissues explains why CAP avoids the toxic effects of myelosuppression while inducing T cell apoptosis to exert the immunosuppressive effect. Therefore, CAP may become an immunosuppressive agent with a simultaneous anti-cancer effect, which is worthy of further studies.
Highlights
Capecitabine (CAP) is widely used in the comprehensive treatment of digestive system tumors
Considering that the conversion of CAP to 5-FU in vivo depends on Thymidylate phosphorylase (TP), we speculated that the reason why CAP did not cause myelosuppression may be related to the lack of expression of TP in bone marrow tissue
Considering that a previous study has confirmed that TP is highly expressed in the liver [9], liver tissue was selected as the positive control, and its TP immunohistochemical (IHC) staining was performed simultaneously with that of bone marrow
Summary
Capecitabine (CAP) is widely used in the comprehensive treatment of digestive system tumors. Capecitabine: A Potential Immunosuppressive Agent rate similar to sorafenib, and that there was no acute rejection during treatment in patients with HCC recurrence after liver transplantation [3] Their findings suggested that CAP may be a potential drug with both immunosuppressive and anti-cancer effects, which has important clinical application value in liver transplantation patients with HCC. Since TP is highly expressed in lymphocytes [9], another characteristic of CAP is the ability to target cancer cells and lymphocytes simultaneously These two pharmacological characteristics provide potential advantages and theoretical basis for us to explore the application of CAP as a drug with both immunosuppressive and anti-cancer effects in liver transplantation patients with HCC. Here, we constructed different doses of CAP mice feeding models to observe the effects of CAP on the immune system of mice, with the idea to provide the basis for understanding and supporting the use of CAP as an immunosuppressive agent with anti-cancer effects to optimize the medication regimen in liver transplant patients with HCC in the future
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