New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer

DNA methylation and histone acetylation are two well known epigenetic chromatin modifications. Epigenetic agents leading to DNA hypomethylation and histone hyperacetylation have been approved for treatment of hematological disorders. The first histone deacetylase inhibitor, vorinostat, has been licensed for cutaneous T cell lymphoma treatment. More than 11 new epigenetic agents are in various stages of clinical development for therapy of multiple cancer types. In this review we summarize novel histone deacetylase inhibitors and new regimens from clinical trials for epigenetic therapy of cancer

Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights

Prognostic markers, such as NPM1, Flt3-ITD, and cytogenetic abnormalities have made it possible to formulate aggressive treatment plans for unfavorable acute myeloid leukemia (AML). However, the long-term survival of AML with unfavorable factors remains unsatisfactory. The latest data indicate that the standard dose of daunorubicin (DNR) at 45 mg/m2 is inferior to high dose 90 mg/m2 for induction therapy. The rates of complete remission and overall survival are significantly better in the high dose induction regimen. New regimens exploring the new liposomal encapsulation of Ara-C and DNR as well as addition of gemtuzumab ozogamicin monoclonal antibody have been studied. New agents, including the nucleoside analogues (clofarabine, sapacitabine, elacytarabine), FLT3 inhibitor (sorafenib), farnesyl-transferase inhibitor (tipifarnib), histone deacetylase inhibitor (vorinostat), lenalidomide, as well as DNA methyltransferase inhibitors (decitabine, azacitidine), were recently reported for AML treatment in the 2009 ASH annual meeting. This review also summarizes the updates of the clinical trials on novel agents including voreloxin, AS1413, behenoylara-C, ARRY520, ribavirin, AZD1152, AZD6244, and terameprocol (EM-1421) from the 2009 ASH annual meeting

An efficient linearly-implicit energy-preserving scheme with fast solver for the fractional nonlinear wave equation

The paper considers the Hamiltonian structure and develops efficient energy-preserving schemes for the nonlinear wave equation with a fractional Laplacian operator. To this end, we first derive the Hamiltonian form of the equation by using the fractional variational derivative and then applying the finite difference method to the original equation to obtain a semi-discrete Hamiltonian system. Furthermore, the scalar auxiliary variable method and extrapolation technique is used to approximate a semi-discrete system to construct an efficient linearly-implicit energy-preserving scheme. A fast solver for the proposed scheme is presented to reduce CPU consumption. Ample numerical results are given to finally confirm the efficiency and conservation of the developed scheme

Hypoacetylation, Hypomethylation, and Dephosphorylation of H2B Histones and Excessive Histone Deacetylase Activity in DU-145 Prostate Cancer Cells

BACKGROUND: Hypoacetylation on histone H3 of human prostate cancer cells has been described. Little is known about the modifications of other histones from prostate cancer cells. METHODS: Histones were isolated from the prostate cancer cell line DU-145 and the non-malignant prostatic cell line RC170N/h. Post-translational modifications of histone H2B were determined by liquid chromatography-mass spectrometry (LC-MS)/MS. RESULTS: The histone H2B of the prostate cancer cell line DU-145 was found to have hypoacetylation, hypomethylation, and dephosphorylation as compared to the non-malignant prostatic cell line RC170N/h. H2B regained acetylation on multiple lysine residues, phosphorylation on Thr19, and methylation on Lys23 and Lys43 in the DU-145 cells after sodium butyrate treatment. CONCLUSIONS: The histone H2B of DU-145 prostate cancer cells are hypoacetylated, hypomethylated, and dephosphorylated. Histone deacetylase inhibitor reversed this phenotype. Epigenetic agent may therefore be useful for prostate cancer therapy and worth further investigation

Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents

Histone deacetylases (HDACs) can regulate expression of tumor suppressor genes and activities of transcriptional factors involved in both cancer initiation and progression through alteration of either DNA or the structural components of chromatin. Recently, the role of gene repression through modulation such as acetylation in cancer patients has been clinically validated with several inhibitors of HDACs. One of the HDAC inhibitors, vorinostat, has been approved by FDA for treating cutaneous T-cell lymphoma (CTCL) for patients with progressive, persistent, or recurrent disease on or following two systemic therapies. Other inhibitors, for example, FK228, PXD101, PCI-24781, ITF2357, MGCD0103, MS-275, valproic acid and LBH589 have also demonstrated therapeutic potential as monotherapy or combination with other anti-tumor drugs in CTCL and other malignancies. At least 80 clinical trials are underway, testing more than eleven different HDAC inhibitory agents including both hematological and solid malignancies. This review focuses on recent development in clinical trials testing HDAC inhibitors as anti-tumor agents

Broadly conserved roles of TMEM131 family proteins in intracellular collagen assembly and secretory cargo trafficking.

Collagen is the most abundant protein in animals. Its dysregulation contributes to aging and many human disorders, including pathological tissue fibrosis in major organs. How premature collagen proteins in the endoplasmic reticulum (ER) assemble and route for secretion remains molecularly undefined. From an RNA interference screen, we identified an uncharacterized Caenorhabditis elegans gene tmem-131, deficiency of which impairs collagen production and activates ER stress response. We find that amino termini of human TMEM131 contain bacterial PapD chaperone-like domains, which recruit premature collagen monomers for proper assembly and secretion. Carboxy termini of TMEM131 interact with TRAPPC8, a component of the TRAPP tethering complex, to drive collagen cargo trafficking from ER to the Golgi. We provide evidence that previously undescribed roles of TMEM131 in collagen recruitment and secretion are evolutionarily conserved in C. elegans, Drosophila, and humans

HSPA12B: A Novel Facilitator of Lung Tumor Growth

Lung tumor progression is regulated by proangiogenic factors. Heat shock protein A12B (HSPA12B) is a recently identified regulator of expression of proangiogenic factors. However, whether HSPA12B plays a role in lung tumor growth is unknown. To address this question, transgenic mice overexpressing HSPA12B (Tg) and wildtype littermates (WT) were implanted with Lewis lung cancer cells to induce lung tumorigenesis. Tg mice showed significantly higher number and bigger size of tumors than WT mice. Tg tumors exhibited increased angiogenesis and proliferation while reduced apoptosis compared with WT tumors. Interestingly, a significantly enhanced upregulation of Cox-2 was detected in Tg tumors than in WT tumors. Also, Tg tumors demonstrated upregulation of VEGF and angiopoietin-1, downregulation of AKAP12, and increased eNOS phosphorylation compared with WT tumors. Celecoxib, a selective Cox-2 inhibitor, suppressed the HSPA12B-induced increase in lung tumor burden. Moreover, celecoxib decreased angiogenesis and proliferation whereas increased apoptosis in Tg tumors. Additionally, celecoxib reduced angiopoietin-1 expression and eNOS phosphorylation but increased AKAP12 levels in Tg tumors. Our results indicate that HSPA12B stimulates lung tumor growth via a Cox-2-dependent mechanism. The present study identified HSPA12B as a novel facilitator of lung tumor growth and a potential therapeutic target for the treatment of lung cancer