Rafoxanide, an organohalogen drug, triggers apoptosis and cell cycle arrest in multiple myeloma by enhancing DNA damage responses and suppressing the p38 MAPK pathway. (1st March 2019)

• Record Type: Journal Article
• Authors: Xiao, Wenqin; Xu, Zhijian; Chang, Shuaikang; Li, Bo; Yu, Dandan; Wu, Huiqun; Xie, Yongsheng; Wang, Yingcong; Xie, Bingqian; Sun, Xi; Kong, Yuanyuan; Lan, Xiucai; Bu, Wenxuan; Chen, Gege; Gao, Lu; Wu, Xiaosong; Shi, Jumei; Zhu, Weiliang
• Is Part Of: Cancer letters. Volume 444(2019)
• Page Start: 45
• Page End: 59
• Publication Date: 2019-03-01
• Subjects: Rafoxanide -- Multiple myeloma -- B-Raf -- DNA damage -- p38 MAPK pathway; MM multiple myeloma -- BM bone marrow -- MMP mitochondrial membrane potential -- MAPK mitogen-activated protein kinase -- ERK extracellular signal-regulated kinase -- BMSC bone marrow stroma cells -- BMMCs bone marrow mononuclear cells -- PBMCs peripheral blood mononuclear cells -- FBS fetal bovine serum -- CCK8 Cell Counting Kit-8 -- IL-6 interleukin-6 -- IGF-1 insulin-like growth factor-1 -- PI propidium iodide -- 7-AAD 7-aminoactinomaycin D -- EdU 5-ethynyl- 2′-deoxyuridine -- HE hematoxylin and eosin -- TUNEL Terminal deoxynucleotidyl transferase dUTP nick end-labeling -- IC50 Half maximal inhibitory concentration -- CI combination index; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.12.014
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: The antitumor activity of rafoxanide have been investigated in MM cell lines both in vitro and in vivo. Rafoxanide overcame the protective effect of the BM microenvironment on myeloma cells. Rafoxanide was cytotoxic, induced cell apoptosis and cell cycle arrest. Rafoxanide enhanced DNA damage responses and suppressed p38 MAPK pathway. Rafoxanide acted synergistically with bortezomib.