Tubacin

Tubacin is a potent, selective, reversible, and cell-permeable inhibitor of HDAC6 with an IC50 value of 4 nM.[1]
Histone deacetylases (HDACs) can be divided into 4 classes, among whom Class I, II, and IV is nuclear zinc-dependent enzymes and Class III is nicotinamide adenine dinucleotide (NAD+) dependent. HDACs catalyze deacetylation of N-acetyl-lysine residues and play an important role in a number of biological reactions including gene expression and cell cycle. By inhibiting α-tubulindeacetylation in mammalian cells, tubacin can suppress the expression of certain genes and therefore result in an antitumor effect without the level of histone acetylation. As selective inhibitors of HDAC6 are used in the treatment of protein degradation disorders, tubacin may have therapeutic applications as antimetastatic and antiangiogenic agent.[1,2]
Tubacin exhibited potent inhibition on HDAC6, with an IC50 value of 4 nM and approximately 350-fold selectivity over HDAC1. In cultured A549 cells, 10 μM tubacin induced up to a 3-fold increase in the relative α-tubulin- acetylation level, with an EC 50 of 2.5 μM. Acute lymphoblastic leukemia (ALL) and normal cells were treated with different concentrations of tubacin ranging from 0.5 to 2.5 mM or controls. The results indicated that tubacin inhibited the growth of ALL cells dose-dependently, with IC50 ranging from 1.2 to 2 mM. Moreover, ALL cells have a greater sensitivity to tubacin compared to other normal cells.[1,2,3]
Tuacin also showed suppressing activity in the growth of ALL cells in vivo. By treating pre-B ALL cells injected mice, the mice in experimental group survival were prolonged comparing with the control. Besides, tubacin treated HEK cells transfected with tau significantly attenuate tau phosphorylation at T231, which also revealed it may play an important role in the pathology of Alzheimer's Disease(AD). [3,4]
Reference:
1.Butler K V, Kalin J, Brochier C, et al. Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A[J]. Journal of the American Chemical Society, 2010, 132(31): 10842-10846.
2.Haggarty S J, Koeller K M, Wong J C, et al. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation[J]. Proceedings of the National Academy of Sciences, 2003, 100(8): 4389-4394.
3.Aldana-Masangkay G I, Rodriguez-Gonzalez A, Lin T, et al. Tubacin suppresses proliferation and induces apoptosis of acute lymphoblastic leukemia cells[J]. Leukemia & lymphoma, 2011, 52(8): 1544-1555.
4.Xu K, Dai X L, Huang H C, et al. Targeting HDACs: a promising therapy for Alzheimer's disease[J]. Oxidative medicine and cellular longevity, 2011, 2011.

The histone deacetylase-6 inhibitor tubacin directly inhibits de novo sphingolipid biosynthesis as an off-target effect.[Pubmed:24835950]

Biochem Biophys Res Commun. 2014 Jul 4;449(3):268-71.

Histone deacetylase 6 (HDAC6) controls acetylation of a number of cytosolic proteins, most prominently tubulin. Tubacin is a small molecule inhibitor of HDAC6 selected for its selective inhibition of HDAC6 relative to other histone deacetylases. For this reason it has become a useful pharmacological tool to discern the biological functions of HDAC6 in numerous cellular processes. The interest of this laboratory is in the function and regulation of sphingolipids, a family of lipids based on the sphingosine backbone. Sphingolipid biosynthesis is initiated by the rate limiting enzyme serine palmitoyltransferase (SPT). Sphingolipids have critical and diverse functions in cell survival, apoptosis, intra- and intercellular signaling, and in membrane structure. In the course of examining the role of HDAC6 in the regulation of sphingolipid biosynthesis we observed that Tubacin strongly inhibited de novo synthesis whereas HDAC6 knockdown very moderately stimulated synthesis. We resolved these seemingly contradictory results by demonstrating that, surprisingly, Tubacin is a direct inhibitor of SPT activity in permeabilized cells. Furthermore Tubacin inhibits de novo sphingolipid synthesis in intact cells at doses commonly used to test HDAC6 function and does so in an HDAC6-independent manner. NilTubacin is a chemical analog of Tubacin which lacks Tubacin's HDAC6 activity, and so is often used as a control for off-target effects of Tubacin. We find that nilTubacin is inactive in the inhibition of sphingolipid biosynthesis, and so does not serve to distinguish the inhibitory effects of Tubacin on HDAC6 from those on sphingolipid biosynthesis. These results indicate that caution should be used in the use of Tubacin to study the role of HDAC6.

[Tubacin promotes Foxp3 expression and suppressive function of mouse CD4+;CD25+; regulatory T cells].[Pubmed:26927553]

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2016 Mar;32(3):339-42.

OBJECTIVE: To observe the changes of fork head transcription factor (Foxp3) expressions and suppressive functions of mouse regulatory T cells (Tregs) after stimulated by Tubacin (histone deacetylase 6 inhibitor) in vitro. METHODS: CD4(+) CD25(+) T and CD4(+) CD25(-) T cells were gained from C57BL/6J mouse spleen lymphocytes by double positive magnetic bead sorting method. Natural Tregs (nTregs) and transforming growth factor beta1 (TGF-beta1)-induced Tregs (iTregs) were stimulated by Tubacin in vitro. Foxp3 expression of each group was identified by reverse transcription PCR, and immunosuppressive activities of each group were tested by the mixed lymphocyte culture (MLC). RESULTS: Foxp3 expression of nTregs and iTregs were significantly enhanced after stimulated with Tubacin. The Tubacin induced CD4(+) CD25(+) Foxp3(high) Tregs significantly inhibited syngeneic CD4(+) CD25(-) T cell activation. CONCLUSION: Tubacin can upregulate Foxp3 expression of CD4(+) CD25(+) Tregs and enhances their cellular immunosuppressive capability.

Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.[Pubmed:23831613]

Brain. 2013 Aug;136(Pt 8):2457-73.

Altered development of the human cerebral cortex can cause severe malformations with often intractable focal epileptic seizures and may participate in common pathologies, notably epilepsy. This raises important conceptual and therapeutic issues. Two missense mutations in the sushi repeat-containing protein SRPX2 had been previously identified in epileptic disorders with or without structural developmental alteration of the speech cortex. In the present study, we aimed to decipher the precise developmental role of SRPX2, to have a better knowledge on the consequences of its mutations, and to start addressing therapeutic issues through the design of an appropriate animal model. Using an in utero Srpx2 silencing approach, we show that SRPX2 influences neuronal migration in the developing rat cerebral cortex. Wild-type, but not the mutant human SRPX2 proteins, rescued the neuronal migration phenotype caused by Srpx2 silencing in utero, and increased alpha-tubulin acetylation. Following in utero Srpx2 silencing, spontaneous epileptiform activity was recorded post-natally. The neuronal migration defects and the post-natal epileptic consequences were prevented early in embryos by maternal administration of tubulin deacetylase inhibitor Tubacin. Hence epileptiform manifestations of developmental origin could be prevented in utero, using a transient and drug-based therapeutic protocol.

Tubacin suppresses proliferation and induces apoptosis of acute lymphoblastic leukemia cells.[Pubmed:21699378]

Leuk Lymphoma. 2011 Aug;52(8):1544-55.

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 alpha-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 alpha-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.

Tubacin is a potent and selective inhibitor of HDAC6, with an IC50 value of 4 nM and approximately 350-fold selectivity over HDAC1.

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