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: Grace I Aldana-Masangkay, Agustin Rodriguez-Gonzalez, Tara Lin, Alan K Ikeda, Yao-Te Hsieh, Yong-Mi Kim, Brett Lomenick, Kazuo Okemoto, Elliot M Landaw, Dongpeng Wang, Ralph Mazitschek, James E Bradner, Kathleen M Sakamoto
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 52 Issue 8 Pg. 1544-55 (Aug 2011) ISSN: 1029-2403 [Electronic] United States
• PMID: 21699378 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anilides
• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Tubulin
• tubacin
• Vincristine
• Poly(ADP-ribose) Polymerases
• HDAC6 protein, human
• Histone Deacetylase 6
• Histone Deacetylases

Topics

• Acetylation (drug effects)
• Anilides (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Synergism
• Histone Deacetylase 6
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Inhibitory Concentration 50
• Jurkat Cells
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Poly(ADP-ribose) Polymerases (metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism, pathology)
• Signal Transduction (drug effects)
• Tubulin (metabolism)
• Vincristine (pharmacology)
• Xenograft Model Antitumor Assays