Potent synergistic interaction between the Nampt inhibitor APO866 and the apoptosis activator TRAIL in human leukemia cells.

19:02 EST 28th November 2014 | BioPortfolio

Summary of "Potent synergistic interaction between the Nampt inhibitor APO866 and the apoptosis activator TRAIL in human leukemia cells."


OBJECTIVE:
The Nampt (nicotinamide phosphoribosyltransferase) inhibitor APO866 depletes intracellular NAD(+) and shows promising anticancer activity in preclinical studies. TNF-Related Apoptosis Inducing Ligand (TRAIL) binds to plasma membrane receptors DR4 and DR5 and induces apoptosis via caspase-8 and -10. Here, we have explored the interaction between APO866 and TRAIL in leukemia cell lines and in primary B-CLL cells.
METHODS:
Cells were treated with APO866, TRAIL, or their combination. Viability and mitochondrial transmembrane potential (DeltaPsi(m)) were determined by cell staining with propidium iodide and TMRE, respectively, and flow cytometry. Nampt and gamma-tubulin levels, as well as caspase-3 cleavage were detected by immunoblotting. DR4 and DR5 expression were assessed by immunostaining and flow cytometry. Caspases were inhibited with zVAD-fmk and zDEVD-fmk; autophagy with 3-MA, LY294002, and wortmannin. Intracellular NAD(+) and ATP were measured by cycling assays and HPLC, respectively.
RESULTS:
APO866 induced NAD(+) depletion, DeltaPsi(m) dissipation, and ATP shortage in leukemia cells, thereby leading to autophagic cell death. TRAIL induced caspase-dependent apoptosis. TRAIL addition to APO866 synergistically increased its activity in leukemia cells by enhancing NAD(+) depletion, DeltaPsi(m) dissipation, and ATP shortage. No DR5 upregulation at the cell surface in response to APO866 was observed. Remarkably, in healthy leukocytes APO866 and TRAIL were poorly active and failed to show any cooperation.
CONCLUSION:
Activation of the extrinsic apoptotic cascade with TRAIL selectively amplifies the sequelae of Nampt inhibition in leukemia cells, and appears as a promising strategy to enhance APO866 activity in hematological malignancies.

Affiliation

Department of Internal Medicine (DIMI), University of Genoa, 16132 Genoa, Italy; Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Journal Details

This article was published in the following journal.

Name: Experimental hematology
ISSN: 1873-2399
Pages:

Links

PubMed Articles [13134 Associated PubMed Articles listed on BioPortfolio]

Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an a...

Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors.

Inhibiting NAD biosynthesis by blocking the function of nicotinamide phosphoribosyl transferase (NAMPT) is an attractive therapeutic strategy for targeting tumor metabolism. However, the development o...

Synergistic Effect of COX-2 Inhibitor on Paclitaxel-Induced Apoptosis in the Human Ovarian Cancer Cell Line OVCAR-3.

Celecoxib, a highly selective cyclooxygenase-2 inhibitor, regulates apoptosis of several types of human cancer cells. The purpose of this study was to investigate whether celecoxib in combination with...

Regulation of NAMPT in Human Gingival Fibroblasts and Biopsies.

Adipokines, such as nicotinamide phosphoribosyltransferase (NAMPT), are molecules, which are produced in adipose tissue. Recent studies suggest that NAMPT might also be produced in the tooth-supportin...

A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis.

TNFα signaling can promote apoptosis or a regulated form of necrosis. ARC (apoptosis repressor with CARD (caspase recruitment domain)) is an endogenous inhibitor of apoptosis that antagonizes both th...

Clinical Trials [1933 Associated Clinical Trials listed on BioPortfolio]

A Study to Assess APO866 for the Treatment of Advanced Melanoma

This phase II study is designed to determine the efficacy and safety of APO866 for the treatment of patients with advanced cutaneous melanoma. APO866 has shown to induce growth inhibition ...

A Study of APO866 for the Treatment of Cutaneous T-cell Lymphoma

This phase II study is designed to determine the efficacy and safety of APO866 for the treatment of patients with advanced forms of cutaneous T-cell lymphoma (CTCL). APO866 has shown to in...

Gefitinib With or Without Simvastatin in Non-Small Cell Lung Cancer (NSCLC)

The epidermal growth factor receptor (EGFR) is a key regulator of growth, differentiation, and survival of epithelial cancers. In a small subset of tumors, the presence of activating mutat...

Effect of Diltiazem Administration on CP-945,598 Pharmacokinetics

A recently completed clinical drug interaction study of CP-945,598 with ketoconazole, a potent CYP3A inhibitor, showed that coadministration of CP-945,598 with ketoconazole results in an a...

Evaluation of Pharmacokinetic Interaction of Indacaterol With Ketoconazole in Healthy Adult Subjects

This study will evaluate the interaction potential between indacaterol and ketoconazole (a potent CYP3A inhibitor) in healthy adult subjects.

Medical and Biotech [MESH] Definitions

A potent inhibitor of ADENOSINE DEAMINASE. The drug induces APOPTOSIS of LYMPHOCYTES, and is used in the treatment of many lymphoproliferative malignancies, particularly HAIRY CELL LEUKEMIA. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity.

A conserved class of proteins that control APOPTOSIS in both VERTEBRATES and INVERTEBRATES. IAP proteins interact with and inhibit CASPASES, and they function as ANTI-APOPTOTIC PROTEINS. The protein class is defined by an approximately 80-amino acid motif called the baculoviral inhibitor of apoptosis repeat.

An inhibitor of apoptosis protein that is translated by a rare cap-independent mechanism. It blocks caspase-mediated cellular destruction by inhibiting CASPASE 3; CASPASE 7; and CASPASE 9.

A technique of culturing mixed cell types in vitro to allow their synergistic or antagonistic interactions, such as on CELL DIFFERENTIATION or APOPTOSIS. Coculture can be of different types of cells, tissues, or organs from normal or disease states.

An inhibitor of apoptosis protein that was initially identified during analysis of CHROMOSOME DELETIONS associated with SPINAL MUSCULAR ATROPHY. Naip contains a nucleotide binding oligomerization domain and a carboxy-terminal LEUCINE rich repeat.

Search BioPortfolio:
Loading
Advertisement

Relevant Topics

The top 5 most promising drugs (February 2014)
Latest News Clinical Trials Research Drugs Reports Corporate
THE FIVE MOST PROMISING DRUGS LAUNCHED OR RECEIVING APPROVAL February 2014 Drug Disease Company Gazyva™ Chronic lymphocytic leukemia Biogen Idec/Genentech/ F. Hoffman-La Roche ...

Cytokine Tumour Necrosis Factor (TNF)
Latest News Clinical Trials Research Drugs Reports Corporate
TNF is a compound that is classified as a cytokine which plays a central role in the cellular mechanisms of apoptosis or cell death. However, there are a number of different kinds of TNF, just under twenty, but the family of molecules have very similar a...

Advertisement