title: Rigosertib induces cell death of a myelodysplastic syndrome-derived cell line by DNA damage-induced G2/M arrest.
abstract: 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 PI3 kinase/Akt pathway. As the effects on cell cycle, rigosertib treatment promoted the phosphorylation of histone H2AX 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 mRNA degradation system. The gene set enrichment analysis showed the suppression of "nonsense-mediated mRNA 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.
authors.affiliation: Division of Medical Technology, Kawasaki College of Allied Health Professions, Okayama, Japan; Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama, Japan; Department of Laboratory Medicine, Kawasaki Medical School, Okayama, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hyoda
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsujioka
authors.forename: Takako
authors.initials: T
authors.lastname: Nakahara
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Suemori
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Okamoto
authors.forename: Mikio
authors.initials: M
authors.lastname: Kataoka
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tohyama
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D020869:Gene Expression Profiling; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008870:Microtubules / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D013450:Sulfones; C507134:ON 01910; C576917:AURKA protein, human; D064096:Aurora Kinase A; D051057:Proto-Oncogene Proteins c-akt; D005998:Glycine
keywords: G2/M arrest; myelodysplastic syndromes; nonsense-mediated mRNA decay; rigosertib; synthetic anticancer agent