title: Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood malignancy, deriving from T-cell progenitors in the thymus, and comprises 10-15% of pediatric and 25% of adult primary ALL cases. Despite advances, 20% of pediatric and the majority of adult patients with T-ALL succumb to mortality from resistant or relapsed disease, and the survival rate for patients with resistant or relapsed T-ALL remains poor. Alterations in the expression of Forkhead box protein M1 (FoxM1) have been detected in several types of cancer, and the inhibition of FoxM1 has been investigated as therapeutic strategy in cancer. The present study investigated the effects of the inhibition of FoxM1 by thiostrepton in human T-ALL Jurkat cells. The cells were treated with different concentrations of thiostrepton, either alone or in combination with doxorubicin. Cell viability was measured using CCK-8 assays and the cell cycle distribution, apoptosis and cell-associated mean fluorescence intensity of intracellular doxorubicin were assessed using flow cytometric analysis. The mRNA and protein expression levels were detected by reverse transcription-quantitative polymerase chain reaction and western blot analyses. The inhibition of FoxM1 by thiostrepton significantly decreased the proliferation of the Jurkat cells proliferation in a time- and dose-dependent manner. Cell arrest at the G2/M phase, and apoptosis was significantly increased in the thiostrepton-treated Jurkat cells. Thiostrepton reduced the half maximal inhibitory concentration of doxorubicin in the Jurkat cells, and significantly enhanced the cytotoxicity of doxorubicin within the Jurkat cells by enhancing doxorubicin-induced apoptosis and increasing the accumulation of intracellular doxorubicin. Furthermore, the inhibition of FoxM1 by thiostrepton enhanced doxorubicin-induced apoptosis, possibly through a caspase-3-dependent pathway, and increased the accumulation of intracellular doxorubicin, possibly through downregulating the expression of glutathione S-transferase pi. Collectively, the results of the present study suggested that targeting FoxM1 with thiostrepton resulted in potent antileukemia activity and chemosensitizing effects in human T-ALL Jurkat cells.
authors.affiliation: Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.
authors.forename: Xiu-Hong
authors.initials: XH
authors.lastname: Jia
authors.affiliation: Department of Respiration, Binzhou People's Hospital, Binzhou, Shandong 256603, P.R. China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Xing
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Tumour Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China.
authors.forename: You-Jie
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Women and Children Hospital of Qingdao, Qingdao, Shandong 266011, P.R. China.
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Fan
authors.affiliation: Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Tumour Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China.
authors.forename: Shu-Yang
authors.initials: SY
authors.lastname: Xie
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis; D006801:Humans; D019169:Jurkat Cells; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D013883:Thiostrepton / Q000008:administration & dosage*
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D004317:Doxorubicin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D013883:Thiostrepton