Abstract
Rafoxanide is used in veterinary medicine for the treatment of fascioliasis. We previously repositioned the drug as the inhibitor of B-Raf V600E, but its anti-tumor effect in human cancer has never been reported. In this study, we investigated the effects of rafoxanide in multiple myeloma (MM) in vitro and in vivo. We found that rafoxanide inhibited cell proliferation and overcame the protective effect of the bone marrow (BM) microenvironment on MM cells. Rafoxanide induced cell apoptosis by reducing mitochondrial membrane potential (MMP) and regulating the caspase pathway, while having no apparent toxic effect on normal cells. Rafoxanide also inhibited DNA synthesis and caused cell cycle arrest by regulating the cdc25A-degradation pathway. In addition, rafoxanide enhanced the DNA damage response by up-regulating the expression of γ-H2AX. Importantly, as a potent B-Raf V600E inhibitor, rafoxanide could suppress activation of the p38 MAPK pathway. Rafoxanide treatment inhibited tumor growth, with no significant side effects, in an MM mouse xenograft model. Finally, combination of rafoxanide with bortezomib or lenalidomide significantly induced synergistic cytotoxicity in MM cells. Collectively, our results may provide a rationale for use of this drug in MM treatment. This study was supported by grants from the National Natural Science Foundation of China (Nos. 81570190; 81670194 and 81529001).
No relevant conflicts of interest to declare.
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