Combination of calcineurin B subunit (CnB) and 5‑fluorouracil reverses 5‑fluorouracil‑induced immunosuppressive effect and enhances the antitumor activity in hepatocellular carcinoma

Zhang,Wenlong; Zhong,Youxiu; Cui,Hongfei; Wang,Liya; Yang,Rui; Su,Zhenyi; Xiang,Benqiong; Wei,Qun

doi:10.3892/ol.2017.6958

Combination of calcineurin B subunit (CnB) and 5‑fluorouracil reverses 5‑fluorouracil‑induced immunosuppressive effect and enhances the antitumor activity in hepatocellular carcinoma

Authors:
- Wenlong Zhang
- Youxiu Zhong
- Hongfei Cui
- Liya Wang
- Rui Yang
- Zhenyi Su
- Benqiong Xiang
- Qun Wei
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Affiliations: Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing Normal University, Beijing 100875, P.R. China
Published online on: September 15, 2017 https://doi.org/10.3892/ol.2017.6958
Pages: 6135-6142

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Abstract

Five‑fluorouracil (5‑FU) is a widely used chemotherapeutic agent for digestive system tumors; however, continuous use of 5‑FU may cause severe side effects, including myelosuppression and immunosuppression. Our previous study revealed that calcineurin B subunit (CnB), an innovative genetic engineering antitumor protein, possesses tumor‑suppressive effects with low toxicity. CnB can bind to and activate integrin αM on macrophages, subsequently promoting the expression, and secretion of TNF‑related apoptosis‑inducing ligand, a specific proapoptotic cytokine. In the present study, whether the combined use of CnB and 5‑FU can reverse the myelosuppression, and immunosuppressive effects of 5‑FU by reactivating the immune system thus increasing antitumor efficacy, was investigated. It was demonstrated that combined treatment of 5‑FU and CnB led to increased tumor‑suppressive effects, as indicated by reduced tumor volume and weight when compared with 5‑FU or CnB treatment alone in a hepatoma xenograph model. In addition, it was demonstrated that combined treatment inhibited the proliferation of hepatoma cells. Notably, the addition of CnB to 5‑FU‑based therapy completely reversed the immunosuppressive effect of 5‑FU. The spleen index and total number of white blood cells in the combination group were higher compared with that of the 5‑FU alone group. Furthermore, pathological examinations indicated that CnB attenuated 5‑FU‑induced organ damage. Based on these findings, it is proposed that CnB may serve as a novel and promising drug candidate for the improvement of 5‑FU‑based chemotherapy.

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