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.

Inhibition of histone deacetylase 6 as a therapeutic strategy for acute lymphocytic leukemia

“…These authors determine that B-and T-acute lymphocytic leukemia (ALL) cells are significantly more sensitive to the anti-proliferative effect of tubacin relative to normal lymphocytes and bone marrow progenitors [3]. In addition, they demonstrate increased apoptosis in tubacin-treated B-and T-ALL cells in comparison to normal lymphocytes.…”

“…Apoptosis of ALL cells was associated with rapid acetylation of a-tubulin and accumulation of ubiquitinated proteins. However, unlike multiple myeloma cells, apoptosis in tubacin-treated ALL cells was independent of Jnk activation [3]. The authors further determine that apoptosis in ALL cells is related to K þ Na þ -ATPase inhibition, a novel mechanism for apoptosis induction in hematologic malignancies.…”

“…HDAC6 has a number of substrates in addition to histones, and many of these approaches are based on inhibiting deacetylation of such non-histone substrates. In various experimental models, HDAC6-inhibition induced pleiotropic effects, including a selective decrease in proliferation and a relative increase in apoptosis in malignant cells as compared to non-transformed cells [1][2][3]. Such effects of HDAC6-inhibition were shown to be independent of histone acetylation state, but were dependent upon acetylation of a-tubulin, one of the alternative HDAC6 substrates.…”

“…In a study published in this issue of Leukemia and Lymphoma, Aldana-Masangkay et al provide important new information regarding the therapeutic potential of HDAC6-inhibition in hematologic malignancies [3]. These authors determine that B-and T-acute lymphocytic leukemia (ALL) cells are significantly more sensitive to the anti-proliferative effect of tubacin relative to normal lymphocytes and bone marrow progenitors [3].…”

Embryonic Life of Hdac Inhibitors: – In Diabetic Nephropathy

“…[22] www.wjpps.com The mechanism of action of HDACIs involves inhibiting the deacetylation of histones.…”