组蛋白脱乙酰基酶抑制剂在肿瘤治疗中的应用

组蛋白的乙酰化状态调控DNA转录从而影响基因的表达水平.组蛋白脱乙酰基酶(HDAC)可降低组蛋白乙酰化,引起DNA-组蛋白复合物压缩.这种压缩可以阻碍基因转录,抑制细胞分化.HDAC抑制剂可以解除DNA-组蛋白复合物压缩,从而促进肿瘤细胞生长停滞、分化及凋亡.在此过程中,HDAC抑制剂也影响非组蛋白的乙酰化状态和功能....     

Histone deacetylase inhibitors induce mitotic slippage

Chromosomal passenger proteins have emerged as key players in the regulation of mitosis and cytokinesis. Histone deacetylase inhibitors (HDACi) are a class of anticancer drugs that induce aberrant mitosis and can overcome the spindle assembly checkpoint. Here, we investigate the mechanism by which HDACi disrupt normal mitotic progression and checkpoint function. We demonstrate that HDACi treatment temporarily delays mitotic progression through prometaphase due to activation of the spindle assembly checkpoint. Despite failing to congress chromosomes to the metaphase plate, cells aberrantly segregate their chromosomes and exit mitosis to undergo a failed cytokinesis. We show that this premature exit from mitosis is a form of mitotic slippage. Chromosomal passenger proteins fail to accumulate at the centromere following HDACi treatment. This results in inadequate concentrations of chromosomal passenger proteins at the centromere, which are insufficient to regulate the phosphorylation of the kinetochore checkpoint component BubR1, and an inability to maintain the mitotic arrest. Thus, the centromeric accumulation of chromosomal passenger complex components is critical for regulating kinetochore but not centromeric processes, and failure of this accumulation underlies the HDACi-induced mitotic slippage.     

Histone deacetylase inhibitors in cancer therapy

Histone deacetylase inhibitors (HDAC inhibitors) represent a novel class of antineoplastic agents that act by promoting acetylation of histones, leading in turn to uncoiling of chromatin and activation of a variety of genes implicated in the regulation of cell surivival, proliferation, differentiation, and apoptosis. The major classes of HDIs include shortchain fatty acids, hydroxamic acid derivatives, synthetic benzamide derivatives, and cyclic tetrapeptides. Members of each of these classes have now entered clinical trials in humans. Despite their shared capacity to trigger histone deacetylation, individual HDIs exert diverse actions on cell cycle regulatory, signal transduction, and survival-related proteins which in all probability accounts for their disparate actions. Major areas of investigation surrounding HDIs include elucidating the mechanisms by which they induce apoptosis in neoplastic cells, and characterizing the factors responsible for the decision of such cells to undergo maturation versus cell death in the response to these agents. In this context, attention has recently focused on the ability of HDIs to induce perturbations in cell cycle regulatory proteins (e.g., p21(CIP1)), downregulation of survival signaling pathways (e.g., Raf/MEK/ERK), and disruption of cellular redox state (e.g., induction of reactive oxygen species; ROS). Aside from efforts to combine HDIs with established cytotoxic drugs, attempts are underway to establish a rational basis for combining HDIs with differentiation- inducing agents (e.g., ATRA, hypomethylating agents such as 5'-deoxyazacytine) with the goal of triggering re-expression of turn or suppressor and/or differentiation-associated genes. Finally, the results of recent preclinical studies provide a strong rationale for combining HDIs with other novel, molecularly targeted agents, including inhibitors of survival signaling pathways or cell cycle progression. Collectively, these findings should provide a fertile environment for the development of novel HDI-containing regimens in the treatment of cancer for many years to come.     

Histone deacetylase inhibitors that target tubulin

Epigenetics is defined as heritable changes in gene expression that occur without changes in DNA sequence. Major mechanisms of epigenetics are post-translational histone modifications such as reversible acetylation. Histone deacetylases (HDACs) maintain the acetylation level of histones but also act on non-histone substrates that are involved in signal transduction or cellular transport processes. One important non-histone substrate is tubulin. The isotypes responsible for tubulin deacetylation are HDAC6 and the NAD⁺-dependent histone deacetylase (sirtuin) Sirt2. Here we review the action of those enzymes on tubulin and present an overview over existing inhibitors with a focus on their structural interaction with the targets.     

Histone deacetylase inhibitors as novel anticancer therapeutics

Histone deacetylase inhibitors represent a promising new class of compounds for the treatment of cancer. Inhibitors of this kind currently under clinical evaluation mainly target the classical (Rpd3/Hda1) family of histone deacetylases. Of particular note, the U.S. Food and Drug Administration recently approved the first histone deacetylase inhibitor (Zolinza: Merck and Co., Whitehouse Station, NJ, U.S.A.) for the treatment of cutaneous T-cell lymphoma. Dozens of such inhibitors are now in phase ii–iii clinical trials, sometimes in combination with other chemotherapy drugs, for diverse cancer types, including both hematologic and solid tumours. In this mini-review, we provide an overview of the histone deacetylase superfamily, highlight the positive results of deacetylase inhibitors in cancer clinical trials, and comment on the prospects for the next generation of such inhibitors.     

Histone deacetylase inhibitors are potent radiation protectants

Radiation-induced acute and late injuries often represent a limit to the optimal delivery of radiotherapy in cancer patients. Chung et al. reported that histone deacetylase (HDAC) inhibitors, a novel class compound of gene modulators, might have a role in controlling different adverse effects from radiotherapy in preclinical models. They also showed how protection of normal tissues and inhibition of tumor growth might be possible at the same time.     

Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor kappaB

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease with a poor prognosis in which nuclear factor kappa B (NF-kappaB) is thought to play a role. This study explored the effects of histone deacetylase inhibitors (HDACIs) MS-275, suberoylanilide hydroxamic acid (SAHA), and LBH589 on both human T-cell lymphotropic virus type I (HTLV-1)-infected T cells (MT-1, -2, -4, and HUT102) and freshly isolated ATL cells harvested from patients. HDACIs effectively inhibited the proliferation of these cells. For example, MS-275, SAHA, and LBH589 effectively inhibited the proliferation of MT-1 cells with ED(50s) of 6microM, 2.5microM, and 100nM, respectively, as measured by 3-(4,5-dimethylithiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay on day 2 of culture. In addition, HDACIs induced cell cycle arrest at the G2/M phase and apoptosis of HTLV-1-infected T-cells in conjunction with regulation of apoptosis-related proteins. Electrophoretic mobility shift assay showed that exposure of HTLV-1-infected T-cells to HDACIs for 48h inhibited formation of the NF-kappaB/DNA binding complex. Moreover, we found that HDACIs accumulated NF-kappaB and inhibitory subunit of NF-kappaB in the cytoplasm in conjunction with the down-regulation of NF-kappaB in the nucleus, suggesting that HDACIs blocked nuclear translocation of NF-kappaB. Based on these findings, we believe HDACIs can be useful for treating patients with ATL or other types of cancer in which NF-kappaB plays a role.     

Histone deacetylase inhibitors: molecular mechanisms of action

This review focuses on the mechanisms of action of histone deacetylase (HDAC) inhibitors (HDACi), a group of recently discovered 'targeted' anticancer agents. There are 18 HDACs, which are generally divided into four classes, based on sequence homology to yeast counterparts. Classical HDACi such as the hydroxamic acid-based vorinostat (also known as SAHA and Zolinza) inhibits classes I, II and IV, but not the NAD+-dependent class III enzymes. In clinical trials, vorinostat has activity against hematologic and solid cancers at doses well tolerated by patients. In addition to histones, HDACs have many other protein substrates involved in regulation of gene expression, cell proliferation and cell death. Inhibition of HDACs causes accumulation of acetylated forms of these proteins, altering their function. Thus, HDACs are more properly called 'lysine deacetylases.' HDACi induces different phenotypes in various transformed cells, including growth arrest, activation of the extrinsic and/or intrinsic apoptotic pathways, autophagic cell death, reactive oxygen species (ROS)-induced cell death, mitotic cell death and senescence. In comparison, normal cells are relatively more resistant to HDACi-induced cell death. The plurality of mechanisms of HDACi-induced cell death reflects both the multiple substrates of HDACs and the heterogeneous patterns of molecular alterations present in different cancer cells.