Rafoxanide, an organohalogen drug, triggers apoptosis and cell cycle arrest in multiple myeloma by enhancing DNA damage responses and suppressing the p38 MAPK pathway.

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Rafoxanide, an organohalogen drug, triggers apoptosis and cell cycle arrest in multiple myeloma by enhancing DNA damage responses and suppressing the p38 MAPK pathway.

Cancer Lett. 2018 Dec 21;:

Authors: Xiao W, Xu Z, Chang S, Li B, Yu D, Wu H, Xie Y, Wang Y, Xie B, Sun X, Kong Y, Lan X, Bu W, Chen G, Gao L, Wu X, Shi J, Zhu W

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, and suppressed activation of the p38 MAPK pathway by down-regulating p38 MAPK phosphorylation and Stat1 phosphorylation. Rafoxanide treatment inhibited tumor growth, with no significant side effects, in an MM mouse xenograft model. Combination of rafoxanide with bortezomib or lenalidomide significantly induced synergistic cytotoxicity in MM cells. Finally, rafoxanide had anti-proliferation effect on both wild type and B-Raf V600E mutated MM cells. And the weaker anti-MM activity of rafoxanide than vemurafenib may indicate other potential mechanisms besides targeting B-Raf V600E mutation. Collectively, our results provide a rationale for use of this drug in MM treatment.

PMID: 30583070 [PubMed - as supplied by publisher]

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