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1.
J Oncol ; 2009: 408038, 2009.
Article in English | MEDLINE | ID: mdl-19547714

ABSTRACT

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently being investigated as a therapeutic agent for a variety of malignancies, as it triggers apoptosis specifically in transformed cells. However, TRAIL use as a stand alone therapeutic is hampered by the fact that many primary tumor cells are resistant to TRAIL-mediated apoptosis. Here, we investigated the extent to which pretreatment of TRAIL-resistant primary B-cell chronic lymphocytic leukemia (B-CLL) cells with histone deacetylase inhibitors (HDACis) could render them susceptible to killing by TRAIL. We found that HDAC inhibition in B-CLL cells led to increased TRAIL receptor expression, increased caspase activation, decreased expression of antiapoptotic regulators such as Bcl-2, and ultimately, enhanced TRAIL-induced apoptosis. Importantly, untransformed peripheral blood mononuclear cells remained largely resistant to TRAIL, even in the presence of HDACis. These results suggest that combination therapies using HDAC inhibition and TRAIL could prove beneficial for the treatment of B-CLL.

2.
Curr Gene Ther ; 9(1): 9-19, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19275567

ABSTRACT

Numerous studies have investigated the potential use of TNF-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic since its discovery in 1995--because TRAIL is a potent inducer of apoptosis in tumor cells but not in normal cells and tissues. Consequently, a great deal is known about TRAIL/TRAIL receptor expression, the molecular components of TRAIL receptor signaling, and methods of altering tumor cell sensitivity to TRAIL-induced apoptosis. Our laboratory was the first to report the possibility of TRAIL gene transfer therapy as an alternative method of using TRAIL as an antitumor therapy. As with recombinant proteins administered systemically, intratumoral TRAIL gene delivery also has limitations that can restrict its full potential. Translating the preclinical TRAIL studies into the clinic has started, with the hope that TRAIL will exhibit robust tumoricidal activity against human primary tumors in situ with minimal toxic side effects.


Subject(s)
Genetic Therapy , Neoplasms/therapy , TNF-Related Apoptosis-Inducing Ligand/genetics , Animals , Clinical Trials as Topic , Humans , Neoplasms/genetics , Neoplasms/pathology , TNF-Related Apoptosis-Inducing Ligand/antagonists & inhibitors , Xenograft Model Antitumor Assays
3.
Apoptosis ; 12(3): 561-71, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17195089

ABSTRACT

Interest in TNF-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic has been high since its first description. Recently, the use of histone deacetylase inhibitors (HDACi) to treat cancer has progressed from the laboratory to the clinic, and the combination of HDACi and TRAIL is very powerful in killing human tumors. Using a panel of prostate tumor cell lines (ALVA-31, DU-145, and LNCaP) with varying TRAIL sensitivity, we examined their sensitization to a recombinant adenovirus encoding TRAIL (Ad5-TRAIL) by sodium butyrate and trichostatin A. HDACi treatment increased coxsackie-adenovirus receptor (CAR) expression, resulting in increased adenoviral infection, and increased TRAIL-mediated killing. In TRAIL-resistant DU-145 cells, HDAC inhibition also decreased protein kinase casein kinase (PKCK) 2 activity, leading to caspase-2 activation. The importance of PKCK2 and caspase-2 in DU-145 sensitization was demonstrated with the PKCK-2-specific inhibitor, which enhanced Ad5-TRAIL-induced death, or the caspase-2-specific inhibitor, zVDVAD, which blocked Ad5-TRAIL-induced death. Thus, our data highlight the connection between HDAC inhibition of PKCK2 activity and tumor cell sensitivity to TRAIL-induced apoptosis. Specifically, HDAC inhibition leads to decreased PCKC2 activity, which is followed by caspase-2 activation and partial cleavage of caspase-8 that sensitizes the tumor cell to TRAIL.


Subject(s)
Adenoviridae/metabolism , Antineoplastic Agents/metabolism , Apoptosis/physiology , Caspase 2/metabolism , Genetic Therapy/methods , Histone Deacetylase Inhibitors , TNF-Related Apoptosis-Inducing Ligand/metabolism , Adenoviridae/genetics , Animals , Caspase 8/metabolism , Cell Line, Tumor , Coxsackie and Adenovirus Receptor-Like Membrane Protein , Enzyme Activation , Histone Deacetylases/metabolism , Humans , Male , Prostatic Neoplasms/metabolism , Receptors, Virus/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , TNF-Related Apoptosis-Inducing Ligand/genetics
4.
Cancer Res ; 66(1): 499-507, 2006 Jan 01.
Article in English | MEDLINE | ID: mdl-16397266

ABSTRACT

Urothelial carcinoma of the bladder accounts for approximately 5% of all cancer deaths in humans. The large majority of tumors are superficial at diagnosis and, after local surgical therapy, have a high rate of local recurrence and progression. Current treatments extend time to recurrence but do not alter disease survival. The objective of the present study was to investigate the tumoricidal potential of combining the apoptosis-inducing protein tumor necrosis factor-related apoptosis inducing ligand (TRAIL) with histone deacetylase inhibitors (HDACi) against TRAIL-resistant bladder tumor cells. Pretreatment with HDACi at nontoxic doses, followed by incubation with TRAIL, resulted in a marked increase in TRAIL-induced apoptosis of T24 cells but showed no significant increase in toxicity to SV40 immortalized normal human uroepithelial cell-1. HDAC inhibition, especially with sodium butyrate and trichostatin A, led to increased TRAIL-R2 gene transcription that correlated with increased TRAIL-R2 surface expression. The increased TRAIL-R2 levels also resulted in accelerated death-inducing signaling complex (DISC) formation, caspase activation, and loss of mitochondrial membrane potential, which all contributed to the increase in tumor cell death. Collectively, these results show the therapeutic potential of combining HDAC inhibition with TRAIL as an alternative treatment for bladder cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis Regulatory Proteins/pharmacology , Histone Deacetylase Inhibitors , Membrane Glycoproteins/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Urinary Bladder Neoplasms/drug therapy , Apoptosis/drug effects , Apoptosis/physiology , Apoptosis Regulatory Proteins/administration & dosage , Apoptosis Regulatory Proteins/genetics , Caspases/metabolism , Cell Line, Tumor , Drug Synergism , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Humans , Intracellular Membranes/drug effects , Intracellular Membranes/physiology , Membrane Glycoproteins/administration & dosage , Membrane Glycoproteins/genetics , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mitochondria/drug effects , Mitochondria/physiology , Receptors, TNF-Related Apoptosis-Inducing Ligand , Receptors, Tumor Necrosis Factor/biosynthesis , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/metabolism , TNF-Related Apoptosis-Inducing Ligand , Transcription, Genetic , Tumor Necrosis Factor-alpha/administration & dosage , Tumor Necrosis Factor-alpha/genetics , Urinary Bladder Neoplasms/enzymology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology
5.
Blood ; 106(10): 3474-82, 2005 Nov 15.
Article in English | MEDLINE | ID: mdl-16037389

ABSTRACT

Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been used to treat bladder cancer for almost 30 years; however, the effector mechanism of the BCG-induced antitumor response remains enigmatic. Most BCG research has focused on the mononuclear-cell infiltrate, but growing evidence supports a role for neutrophils in the antitumor response. Previously, we demonstrated increased urinary tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo-2L) levels from BCG-responsive patients compared to nonresponders. Interestingly, neutrophils isolated from the urine expressed TRAIL/Apo-2L, leading us to investigate the neutrophil response to BCG. BCG-stimulated neutrophils expressed surface-bound and released functional soluble TRAIL/Apo-2L. Whereas neither interferon alpha (IFN-alpha) nor IFN-gamma directly induced TRAIL/Apo2L expression by neutrophils, IFN-alpha did stimulate TRAIL gene transcription, and IFN-primed neutrophils contained and released more TRAIL/Apo-2L after BCG stimulation than did unprimed neutrophils. In unstimulated neutrophils TRAIL/Apo-2L was present predominantly in the azurophilic granules and plasma-membrane-enriched/secretory-granule fraction. Finally, we observed that killed BCG, Toll-like receptor 2 (TLR2) and TLR4 agonists, and an M tuberculosis cell-wall fraction were each capable of inducing the release of soluble TRAIL/Apo-2L from neutrophils. These results further characterize the potential role neutrophils may play in initiating the antitumor response described with BCG treatment for superficial bladder cancer.


Subject(s)
Apoptosis Regulatory Proteins/metabolism , Membrane Glycoproteins/metabolism , Mycobacterium bovis/immunology , Neutrophil Activation/immunology , Neutrophils/metabolism , Tumor Necrosis Factor-alpha/metabolism , Antineoplastic Agents/pharmacology , Apoptosis Regulatory Proteins/immunology , Cell Wall/chemistry , Cells, Cultured , Complex Mixtures/chemistry , Complex Mixtures/pharmacology , Humans , Interferon-alpha/pharmacology , Interferon-gamma/pharmacology , Membrane Glycoproteins/immunology , Neutrophil Activation/drug effects , Neutrophils/immunology , Neutrophils/microbiology , Secretory Vesicles/immunology , Secretory Vesicles/metabolism , TNF-Related Apoptosis-Inducing Ligand , Toll-Like Receptor 2/antagonists & inhibitors , Toll-Like Receptor 2/immunology , Toll-Like Receptor 4/antagonists & inhibitors , Toll-Like Receptor 4/immunology , Tumor Necrosis Factor-alpha/immunology , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/microbiology , Urinary Bladder Neoplasms/therapy
6.
Hum Pathol ; 35(9): 1156-9, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15343519

ABSTRACT

An insular cortex tumor in a 54-year-old woman showed unequivocal neurocytic features, including open nuclei, distinct nucleoli, and strong synaptophysin immunoreactivity. Ultrastructurally, there were neuritic-type processes with microtubules and hillock-like attachments, and there were dense-core granules. Atypical features were mitotic activity, prominent vasculature, and small foci of necrosis. Peripherally, there was oligodendroglia-like histology with single-cell infiltration of white matter and perineuronal spread in cortex. Fluorescence in situ hybridization analysis with chromosome 1 and 19 probes showed 3 copies of 1q and 2 copies of 1p and showed 2 copies of 19q and 4 copies of 19p. This yielded a 1p-19q loss of heterozygosity pattern similar to that seen in oligodendrogliomas, although the actual chromosomal abnormality is distinct. This tumor, best classified as an atypical neurocytoma with oligodendroglia-like spread, supports suggestions of a close histogenic relationship between oligodendroglial and neurocytic tumors. This case also illustrates the limitations of relying exclusively on loss of heterozygosity analysis for tumor classification.


Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/pathology , Neurocytoma/genetics , Neurocytoma/pathology , Oligodendroglioma/pathology , Brain Neoplasms/classification , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 19 , Diagnosis, Differential , Female , Gene Dosage , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Loss of Heterozygosity , Microscopy, Electron , Middle Aged , Neurocytoma/classification , Oligodendroglioma/classification , Oligodendroglioma/ultrastructure
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