Open AccessRigosertib induces cell death of a myelodysplastic syndrome‐derived cell line by DNA damage‐induced G2/M arrest
Author(s) -
Hyoda Tomoko,
Tsujioka Takayuki,
Nakahara Takako,
Suemori Shinichiro,
Okamoto Shuichiro,
Kataoka Mikio,
Tohyama Kaoru
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12605
Subject(s) - cell cycle , apoptosis , downregulation and upregulation , haematopoiesis , dna damage , cancer research , cell cycle checkpoint , biology , cell culture , myelodysplastic syndromes , microbiology and biotechnology , mitosis , parp1 , immunology , gene , poly adp ribose polymerase , bone marrow , genetics , stem cell , dna , polymerase
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.