title: 10058-F4, a c-Myc inhibitor, markedly increases valproic acid-induced cell death in Jurkat and CCRF-CEM T-lymphoblastic leukemia cells.
abstract: Adult T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis. Although it has been found that activation of Notch1 signaling occurs in >50% T-ALL patients, γ-secretase inhibitors that target Notch1 signaling are of limited efficacy. However, c-Myc is an important direct target of Notch1 and, thus, c-Myc is another potential therapeutic target for T-ALL. Valproic acid (VPA), a histone deacetylase inhibitor, has been reported to treat various hematological malignancies. In the present study, we showed that c-Myc expression, at a transcriptional level, was dose-dependently downregulated in VPA-induced growth inhibition in T-ALL cell lines, Jurkat and CCRF-CEM cells. 10058-F4, a small molecule c-Myc inhibitor, could increase the downregulation of c-Myc and markedly increase the growth inhibition and cell death induced by VPA in Jurkat and CCRF-CEM cells, which was accompanied by obvious cleavage of capase-3. Z-VAD-FMK, a caspase inhibitor, partially prevented the anti-leukemic effect. The results of the present study suggest that c-Myc inhibitors increase cell death induced by VPA in a caspase-dependent and -independent manner, and their combination could be a potent therapeutic strategy for adult T-ALL patients.
authors.affiliation: Department of Hematology, Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310003, P.R. China ; Key Laboratory of Hematopoietic Malignancies of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China ; Laboratory of Stem Cell Transplantation, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Qitian
authors.initials: Q
authors.lastname: Mu
authors.affiliation: Department of Hematology, Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310003, P.R. China ; Key Laboratory of Hematopoietic Malignancies of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Qiuling
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Hematology, Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310003, P.R. China ; Key Laboratory of Hematopoietic Malignancies of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Hematology, Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310003, P.R. China ; Key Laboratory of Hematopoietic Malignancies of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310003, P.R. China ; Key Laboratory of Hematopoietic Malignancies of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Mengxia
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Hematology, Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310003, P.R. China ; Key Laboratory of Hematopoietic Malignancies of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Hematology, Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310003, P.R. China ; Key Laboratory of Hematopoietic Malignancies of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Hematology, Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310003, P.R. China ; Key Laboratory of Hematopoietic Malignancies of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
keywords: CCRF-CEM; Jurkat; T-cell acute lymphoblastic leukemia; c-Myc inhibitors; cell death; valproic acid