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 (IC₅₀) 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.

Keywords:

• Tubacin
• HDAC6
• ALL
• aggresome pathway

Acknowledgements

This work was supported by the Jonsson Comprehensive Cancer Center Seed Grant (A.R.-G. and K.M.S.), and the William Lawrence and Blanche Hughes Foundation. K.M.S. is a recipient of National Institutes of Health (NIH) R01 grants HL75826 and HL83077 and the St. Baldrick's Foundation Research Award. K.M.S. and M.M. are Scholars of the Leukemia and Lymphoma Society. D.W. and R.M. are funded by NIH grant P50-CA86355. G.I.A.-M. is supported by the Eugene Cota-Robles Fellowship (ECR) grant and a Minority Supplement from NIH R01HL075826. We also would like to thank Marküs Muschen for providing the expression profile data and reading the manuscript; and James Ch'ng for his technical assistance.

Potential conflict of interest:

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