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

Abstract

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.

Cordycepin suppresses the migration and invasion of human liver cancer cells by downregulating the expression of CXCR4

“…The treatment of liver cancer remains predominantly based on surgical resection combined with radio-, chemo- and targeted therapy, which inhibit the malignant proliferation of liver cancer cells, but do not inhibit tumor metastasis (6,12). For example, 5-fluorouracil and cisplatin primarily inhibit liver cancer cell proliferation and induce apoptosis (38-40). Sorafenib, a first-line liver cancer drug, inhibits angiogenesis of liver cancer cells, thereby cutting off the blood supply to tumors and inhibiting the proliferation of tumor cells (41,42).…”