title: Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome.
abstract: Rigosertib has demonstrated therapeutic activity for patients with high-risk myelodysplastic syndrome (MDS) in clinical trials. However, the role of rigosertib in MDS has not been thoroughly characterized. In this study, we found out that rigosertib induced apoptosis, blocked the cell cycle at the G2/M phase and subsequently inhibited the proliferation of CD34+ cells from MDS, while it minimally affected the normal CD34+ cells. Further studies showed that rigosertib acted via the activation of the P53 signaling pathway. Bioinformatics analysis based on gene expression profile and flow cytometry analysis revealed the abnormal activation of the Akt-PI3K, Jak-STAT and Wnt pathways in high-grade MDS, while the p38 MAPK, SAPK/JNK and P53 pathways were abnormally activated in low-grade MDS. Rigosertib could markedly inhibit the activation of the Akt-PI3K and Wnt pathways, whereas it activated the SAPK/JNK and P53 pathways in high-grade MDS. A receptor tyrosine kinase phosphorylation array demonstrated that rigosertib could increase the activation of RET and PDGFR-β while reducing the activation of Tie2 and VEGFR2 in MDS cells. Taken together, these data indicate that rigosertib is a selective and promising anti-tumor agent that could ameliorate multiple dysregulated signaling transduction pathways in high-grade MDS.
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Qi
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Chun-Kang
authors.initials: CK
authors.lastname: Chang
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Wu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Shi
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: You-Shan
authors.initials: YS
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Shu-Cheng
authors.initials: SC
authors.lastname: Gu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Fei
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Juan
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Dong
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital.
authors.forename: Liyu
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050791:STAT Transcription Factors; D015398:Signal Transduction / Q000187:drug effects*; D013450:Sulfones / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050791:STAT Transcription Factors; D013450:Sulfones; D016159:Tumor Suppressor Protein p53; C507134:ON 01910; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D005998:Glycine