Deoxyribonucleic acid methyltransferase 3B promotes epigenetic silencing through histone 3 chromatin modifications in pituitary cells.

Context And Objective: Epigenetic dysregulation is implicated in pituitary neoplasia as the cause of silencing of several tumor suppressor genes. However, the upstream mediators of such events remain unknown.

Design: We examined the three members of the DNA methyltransferase (DNMT) enzyme family in normal and neoplastic human and mouse pituitary cells.

TROSY-based NMR evidence for a novel class of 20S proteasome inhibitors.

The proteasome plays a central role in maintaining cellular homeostasis, in controlling the cell cycle, in removing misfolded proteins that can be toxic, and in regulating the immune system. It is also an important target for novel anticancer drugs, such as bortezomib, a potent inhibitor that has been used successfully in the treatment of multiple myeloma. Here, we show that the antimalaria drug chloroquine inhibits proteasome function in eukaryotic cell extracts and in preparations of purified 20S archaeal proteasome from Thermoplasma acidophilium.

Cyproheptadine displays preclinical activity in myeloma and leukemia.

D-cyclins are regulators of cell division that act in a complex with cyclin-dependent kinases to commit cells to a program of DNA replication. D-cyclins are overexpressed in many tumors, including multiple myeloma and leukemia, and contribute to disease progression and chemoresistance. To better understand the role and impact of D-cyclins in hematologic malignancies, we conducted a high throughput screen for inhibitors of the cyclin D2 promoter and identified the drug cyproheptadine.

Pharmaceutical excipients inhibit cytochrome P450 activity in cell free systems and after systemic administration.

Excipients are largely used as inert vehicles in formulation. Recent studies indicated that some excipients could affect drug transport and disposition. But the effects of most excipients on drug metabolism are yet to be unveiled.

Bcl-B expression in human epithelial and nonepithelial malignancies.

Purpose: Apoptosis plays an important role in neoplastic processes. Bcl-B is an antiapoptotic Bcl-2 family member, which is known to change its phenotype upon binding to Nur77/TR3. The expression pattern of this protein in human malignancies has not been reported.

Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity.

Knockout and transgenic studies in mice demonstrate that normal somatic tissues redundantly express 3 cyclin D proteins, whereas tumor cells seem dependent on a single overexpressed cyclin D. Thus, selective suppression of the individual cyclin D deregulated in a tumor represents a biologically valid approach to targeted cancer therapy. In multiple myeloma, overexpression of 1 of the cyclin D proteins is a ubiquitous feature, unifying at least 7 different initiating genetic events.

A novel diquinolonium displays preclinical anti-cancer activity and induces caspase-independent cell death.

Quinolines are a class of chemical compounds with emerging anti-cancer properties. Here, we tested the activity of series of quinolines and quinoline-like molecules for anti-cancer activity and identified a novel diquinoline, 1-methyl-2-[3-(1-methyl-1,2-dihydroquinolin-2-yliden)prop-1-enyl]quinolinium iodide (Q(2)). Q(2 )induced cell death in leukemia, myeloma, and solid tumor cell lines with LD50s in the low to submicromolar range.

Apoptosis in leukemia: from molecular pathways to targeted therapies.

Knowledge about apoptosis pathways developed in the last few years is already being translated into novel targeted therapies. Two illustrative approaches to this process are the development of small molecule BCL2 inhibitors and X-linked inhibitors of apoptosis proteins (XIAP) inhibitors. This work demonstrates both the development of new agents based on molecular mechanisms and how these agents further our understanding of the biology of apoptosis.

Outcome of patients who develop acute leukemia or myelodysplasia as a second malignancy after solid tumors treated surgically or with strategies that include chemotherapy and/or radiation.

Background: Evaluation of therapeutic outcomes and risk factors was undertaken for patients with primary solid tumors (PST) developing acute leukemia or myelodysplasia (MDS) as a second malignancy.

Methods: In all, 131 consecutive patients presenting to a single institution with leukemia or MDS after treatment for PST with surgery or chemotherapy/radiotherapy were examined. Management of the secondary acute leukemia and MDS consisted either of intensive therapy including allogeneic blood and marrow transplants or supportive measures.

SBDS-deficient cells undergo accelerated apoptosis through the Fas-pathway.

Background: Shwachman-Diamond syndrome is an inherited multisystem disorder characterized by bone marrow and pancreatic dysfunction as well as metaphyseal dysostosis. Ninety percent of the patients have mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS). The relationship between SBDS and cell survival is unknown.

A high-content chemical screen identifies ellipticine as a modulator of p53 nuclear localization.

p53 regulates apoptosis and the cell cycle through actions in the nucleus and cytoplasm. Altering the subcellular localization of p53 can alter its biological function. Therefore, small molecules that change the localization of p53 would be useful chemical probes to understand the influence of subcellular localization on the function of p53.

Novel therapies targeting the apoptosis pathway for the treatment of acute myeloid leukemia.

Defects in the core regulators of the apoptosis pathway contribute to chemoresistance and poor outcomes in patients with acute myeloid leukemia (AML). To overcome these defects, novel molecules that target key proteins in the mitochondrial, death receptor, and convergence pathways of caspase activation are being developed. This review will highlight selected molecules including Bcl-2 and XIAP inhibitors that are advanced stages of development and have entered clinical trial for AML.

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin.

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation.

A chemical screen identifies anisomycin as an anoikis sensitizer that functions by decreasing FLIP protein synthesis.

Malignant epithelial cells with metastatic potential resist apoptosis that normally occurs upon loss of anchorage from the extracellular matrix, a process termed "anoikis." Resistance to anoikis enables malignant cells to survive in an anchorage-independent manner, which leads to the formation of distant metastases. To understand the regulation of anoikis, we designed, automated, and conducted a high-throughput chemical screen for anoikis sensitizers.

Predictors of response to reinduction chemotherapy for patients with acute myeloid leukemia who do not achieve complete remission with frontline induction chemotherapy.

Eighty-one patients with acute myeloid leukemia who had persistent leukemia following standard induction therapy with cytarabine plus daunorubicin (7+3 regimen) underwent reinduction therapy with a combination of mitoxantrone, etoposide, and high-dose cytarabine (HiDAC). Patients achieving complete remission (CR) then received consolidation therapy with HiDAC plus mitoxantrone. Patients with matched sibling donors were referred for allogeneic bone marrow transplantation (BMT) in CR-1.

Critical role for Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein in anoikis resistance and distant tumor formation.

Background: Normal epithelial cells undergo anoikis, or apoptosis on loss of anchorage to the extracellular matrix, by initiating the death receptor pathway of caspase activation. However, malignant epithelial cells with metastatic potential resist anoikis and can survive in an anchorage-independent fashion. We hypothesized that c-Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein (FLIP), an endogenous inhibitor of death receptor signaling, may suppress anoikis.

Characteristics and outcomes of acute myelogenous leukemia patients with very late relapse (>5 years).

The clinical characteristics and outcome of 15 patients with acute myelogenous leukemia (AML) who experienced relapse at least 5 years after induction of complete remission (very late-relapse AML) are described. This subgroup represented 3% of all relapsed patients seen at this institution over the same time period. There were eight males in this cohort and the median age at diagnosis was 48 years (range 13 - 77 years).

Myelodysplastic syndromes: the complexity of stem-cell diseases.

The prevalence of patients with myelodysplastic syndromes (MDS) is increasing owing to an ageing population and increased awareness of these diseases. MDS represent many different conditions, not just a single disease, that are grouped together by several clinical characteristics. A striking feature of MDS is genetic instability, and a large proportion of cases result in acute myeloid leukaemia (AML).

Livin/melanoma inhibitor of apoptosis protein as a potential therapeutic target for the treatment of malignancy.

Livin, also called melanoma inhibitor of apoptosis protein (IAP) or kidney IAP, is a member of the IAP family of caspase inhibitors that selectively binds the endogenous IAP antagonist SMAC and caspase-3, caspase-7, and caspase-9. As such, Livin inhibits apoptosis, and its overexpression renders malignant cells resistant to chemotherapy. Therefore, inhibitors of Livin could be useful adjuncts to chemotherapy in the treatment of malignancies.

Induction of apoptosis in lymphoid and myeloid leukemia.

Defects in the core machinery of the apoptosis pathway contribute to chemoresistance and poor outcomes in patients with acute leukemia. To overcome these defects, novel molecules that target key proteins in the apoptosis pathway are being developed. This review highlights compounds that target the mitochondrial, death receptor, and convergence pathways of caspase activation that are being developed for the treatment of acute leukemia.