Synergistic Induction of Apoptosis in Primary B-CLL Cells after Treatment with Recombinant Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and Histone Deacetylase Inhibitors.

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.

TRAIL gene therapy: from preclinical development to clinical application.

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.

Activation of tumor-specific CD8+ T Cells after intratumoral Ad5-TRAIL/CpG oligodeoxynucleotide combination therapy.

CD8(+) T-cell activation via cross-presentation of antigens from apoptotic tumor cells is controversial. Dendritic cells capture naturally shed tumor antigens and cross-present them to CD8(+) T cells; unfortunately, the frequency of activated CD8(+) T cells is often too low to mount an effective response against the tumor. By increasing the amount of antigen for presentation, a larger T-cell response can be theoretically elicited.

Apoptotic cells induce tolerance by generating helpless CD8+ T cells that produce TRAIL.

The decision to generate a productive immune response or immune tolerance following pathogenic insult often depends on the context in which T cells first encounter Ag. The presence of apoptotic cells favors the induction of tolerance, whereas immune responses generated with necrotic cells promote immunity. We have examined the tolerance induced by injection of apoptotic cells, a system in which cross-presentation of Ag associated with the dead cells induces CD8+ regulatory (or suppressor) T cells.

Histone deacetylase inhibitors enhance Ad5-TRAIL killing of TRAIL-resistant prostate tumor cells through increased caspase-2 activity.

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.

Histone deacetylase inhibitors modulate the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand-resistant bladder tumor cells.

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.

Histone deacetylase inhibitors modulate renal cell carcinoma sensitivity to TRAIL/Apo-2L-induced apoptosis by enhancing TRAIL-R2 expression.

Every year, 12,000 people in the U.S. die from renal cell carcinoma.

Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guerin (BCG) results in the release of functional soluble TRAIL/Apo-2L.

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.

Depsipeptide (FR901228) enhances the cytotoxic activity of TRAIL by redistributing TRAIL receptor to membrane lipid rafts.

TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis in various tumor cell types and is under investigation as a cancer therapeutic. The development of a recombinant adenovirus encoding the full-length human TRAIL gene (Ad5-TRAIL) replaces the need for large quantities of soluble TRAIL protein in tumor suppressive therapies. However, the full potential of Ad5-TRAIL has not yet been maximized.