Capecitabine Can Induce T Cell Apoptosis: A Potential Immunosuppressive Agent With Anti-Cancer Effect

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.

Capecitabine Regulates HSP90AB1 Expression and Induces Apoptosis via Akt/SMARCC1/AP-1/ROS Axis in T Cells

“…All animals were obtained from China National Institutes for Food and Drug Control. Male Balb/c mice aged 6–8 weeks were gavaged with metronomic doses of CAP (100 mg/kg/day) (Solarbio, Beijing, China) [ 12 , 35 ]. At days 0, 7, 14, and 21, mice ( n = 10) were sacrificed.…”

“…CAP is the first-line therapeutic drug for CRC, and some clinical studies have also confirmed that CAP, especially at the dosage used in metronomic chemotherapy (a novel type of chemotherapy featuring low dosage and uninterrupted administration), has a good effect in treating HCC [ 8 – 11 ]. In addition, the expression of TP in T cells has been confirmed, which lays the pharmacodynamics foundation for the conversion of CAP to 5-FU in T cells [ 12 ]. Earlier experiments showed that CAP can induce apoptosis in T cells, which confirmed this view [ 12 ].…”

“…In addition, the expression of TP in T cells has been confirmed, which lays the pharmacodynamics foundation for the conversion of CAP to 5-FU in T cells [ 12 ]. Earlier experiments showed that CAP can induce apoptosis in T cells, which confirmed this view [ 12 ]. Therefore, CAP may be a potential immunosuppressant with an antitumor effect.…”

“…As oxygen-containing chemically reactive molecules, ROS are closely related to T cell apoptosis and activation [ 21 ]. On this basis, we explored the immunosuppressive effect of CAP and recently showed that CAP can induce T cell ROS production, subsequently leading to apoptosis, but the molecular mechanism behind it is still unknown [ 12 ]. In recent years, the development of mass spectrometry technology has made it possible to identify proteins on a large scale, which enables the underlying mechanism behind the immunosuppressive effect of CAP to be explored [ 22 – 24 ].…”

“…Previous studies have demonstrated that AP-1 can regulate GCLM and HO-1 expression, which in turn influences the production of ROS [ 33 ]. ROS production, as previously mentioned, is closely associated with apoptosis [ 12 , 21 , 34 ]. It was hypothesized that targeted inhibition of HSP90AB1 could inhibit Akt/SMARCC1/AP-1 axis to induce ROS production and lead to T cell apoptosis by CAP.…”