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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. [ABSTRACT FROM AUTHOR]

Metastasis is a crucial hallmark of cancer progression, which involves numerous factors including the degradation of the extracellular matrix (ECM), the epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, the development of an inflammatory tumor microenvironment, and defects in programmed cell death. Programmed cell death, such as apoptosis, autophagy, and necroptosis, plays crucial roles in metastatic processes. Malignant tumor cells must overcome these various forms of cell death to metastasize. This review summarizes the recent advances in the understanding of the mechanisms by which key regulators of apoptosis, autophagy, and necroptosis participate in cancer metastasis and discusses the crosstalk between apoptosis, autophagy, and necroptosis involved in the regulation of cancer metastasis. [ABSTRACT FROM AUTHOR]