title: Tubacin suppresses proliferation and induces apoptosis of acute lymphoblastic leukemia cells.
abstract: Over the past decade, histone deacetylase inhibitors have increasingly been used to treat various malignancies. Tubacin (tubulin acetylation inducer) is a small molecule that inhibits histone deacetylase 6 (HDAC6) and induces acetylation of α-tubulin. We observed a higher antiproliferative effect of tubacin in acute lymphoblastic leukemia (ALL) cells than in normal hematopoietic cells. Treatment with tubacin led to the induction of apoptotic pathways in both pre-B and T cell ALL cells at a 50% inhibitory concentration (IC(50)) of low micromolar concentrations. Acetylation of α-tubulin increases within the first 30 min following treatment of ALL cells with tubacin. We also observed an accumulation of polyubiquitinated proteins and poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the signaling pathways activated by tubacin appear to be distinct from those observed in multiple myeloma. In this article, we demonstrate that tubacin enhances the effects of chemotherapy to treat primary ALL cells in vitro and in vivo. These results suggest that targeting HDAC6 alone or in combination with chemotherapy could provide a novel approach to treat ALL.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
authors.forename: Grace I
authors.initials: GI
authors.lastname: Aldana-Masangkay
authors.forename: Agustin
authors.initials: A
authors.lastname: Rodriguez-Gonzalez
authors.forename: Tara
authors.initials: T
authors.lastname: Lin
authors.forename: Alan K
authors.initials: AK
authors.lastname: Ikeda
authors.forename: Yao-Te
authors.initials: YT
authors.lastname: Hsieh
authors.forename: Yong-Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Brett
authors.initials: B
authors.lastname: Lomenick
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okemoto
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Landaw
authors.forename: Dongpeng
authors.initials: D
authors.lastname: Wang
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Sakamoto
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014404:Tubulin; C474316:tubacin; D014750:Vincristine; D011065:Poly(ADP-ribose) Polymerases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases