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A multi‐kinase inhibitor, rigosertib ( ON  01910.Na) has recently been highlighted as a novel type of anti‐cancer agent for the treatment of the myelodysplastic syndromes ( MDS ), but its action mechanisms remain to be clarified. We investigated the  in vitro  effects of rigosertib on an  MDS ‐derived cell line  MDS ‐L and a myeloid leukemia cell line  HL ‐60. Rigosertib suppressed the proliferation of both  HL ‐60 and  MDS ‐L cells and induced apoptosis by inhibition of the  PI 3 kinase/Akt pathway. As the effects on cell cycle, rigosertib treatment promoted the phosphorylation of histone H2 AX  and led to the  DNA  damage‐induced G2/M arrest. In addition, an immunofluorescence staining study demonstrated the abnormal localization of aurora A kinase, suggesting that rigosertib causes perturbation of spindle assembly and deregulated mitotic patterns towards cell cycle arrest and apoptosis. We also found that rigosertib exerted growth inhibitory effects on two lymphoid cell lines, Jurkat and Ramos. We further examined the molecular pathways influenced by rigosertib from the gene expression profiling data of  MDS ‐L cells and found a possible involvement of rigosertib treatment in the upregulation of the genes related to microtubule kinetics and the downregulation of the m RNA  degradation system. The gene set enrichment analysis showed the suppression of “nonsense‐mediated m RNA  decay ( NMD )” as the most significantly affected gene set. These data provide a new aspect and a potential utility of rigosertib for the treatment of refractory hematopoietic malignancies.

Rigosertib induces cell death of a myelodysplastic syndrome‐derived cell line by DNA damage‐induced G2/M arrest