title: Givinostat, a type II histone deacetylase inhibitor, induces potent caspase-dependent apoptosis in human lymphoblastic leukemia.
abstract: Unlike chronic myeloid leukemia, patients with acute lymphoblastic leukemia (ALL) with Philadelphia chromosome (Ph+) do not respond well to Imatinib or tyrosine kinase inhibitors (TKI). In addition, TKI might induce resistant mutations in kinase domain (KD) ofABLin patients with relapsed diseases. Of the histone deacetylase (HDAC) inhibitors, suberoylanilide hydroxamic acid (SAHA) has shown to induce potent cytotoxicity on acute myeloid leukemia cell lines but Givinostat effect on acute lymphoblastic leukemia (ALL) has not been reported. We investigated if Givinostat could exert similar inhibitory effect on SUP-B15, an established B-cell ALL with Philadelphia chromosome (Ph+). TwoPh+ leukemia cell lines, SUP-B15 and an AML cell line K562 were studied in parallel for their responses to Givinostat. Mutation status ofTP53genes was also examined to correlate cellular proliferation and apoptosis. Givinostat significantly inhibited cell proliferation of SUP-B15 (IC50:0.18±0.03μM) and simultaneously inhibited BCR-ABL signal pathway. A remarkable apoptosis was induced by 0.25μM Givinostat in SUP-B15 along with the activation of caspase cascades and increased expression of p21. These inhibitory and proapoptotic effects were not observed in K562 simultaneously treated with Givinostat. Finally our studies showed thatTP53mutation status might determine responder or non-responder to Givinostat in these twoPh+leukemia cell lines.
authors.affiliation: The Third Xiangya Hospital of Central South University, Hunan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Zhao
authors.affiliation: The Third Xiangya Hospital of Central South University, Hunan, China.
authors.forename: Chenjiao
authors.initials: C
authors.lastname: Yao
authors.affiliation: Department of Pathology, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Kahwash
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Guojiuan
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Patterson
authors.affiliation: Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Wang
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
keywords: BCR-ABL; acute lymphoblastic leukemia; apoptosis; givinostat; p53