In vitro efficacy of AdTRAIL gene therapy of bladder cancer is enhanced by trichostatin A-mediated restoration of CAR expression and downregulation of cFLIP and Bcl-XL

El-Zawahry, Ahmed; Lü, Ping; White, Shai J.; Voelkel‐Johnson, Christina

doi:10.1038/sj.cgt.7700905

Cited by 32 publications

(32 citation statements)

References 34 publications

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“…[12][13][14]19 However, here we show that HDACi can also further increase transgene expression in CAR-positive cells. The ability of HDACi to increase adenoviral transgene expression appears to be limited to malignant cells, since it has not been observed in normal cells isolated from breast, liver, kidney and, as shown in this study, prostate.…”

Section: Discussionmentioning

confidence: 97%

“…9,10 Some agents, including the DNA damaging agent etoposide and a new class of chemotherapeutic agents known as histone deacetylase inhibitors (HDACi) increase adenoviral transgene expression, thereby potentially lowering the amount of adenovirus required to achieve a therapeutic response. [11][12][13][14] The mechanism by which HDACi's increase adenoviral transgene expression has been attributed to restoration of CAR expression. [12][13][14] The goal of this study was to determine which chemotherapeutic agents would be suitable for combination with gene therapy in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] The mechanism by which HDACi's increase adenoviral transgene expression has been attributed to restoration of CAR expression. [12][13][14] The goal of this study was to determine which chemotherapeutic agents would be suitable for combination with gene therapy in prostate cancer. Prostate cancer remains a leading cause of cancer death among American men.…”

Section: Introductionmentioning

confidence: 99%

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The histone deacetylase inhibitors depsipeptide and MS-275, enhance TRAIL gene therapy of LNCaP prostate cancer cells without adverse effects in normal prostate epithelial cells

2006

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The histone deacetylase inhibitors depsipeptide and MS-275, enhance TRAIL gene therapy of LNCaP prostate cancer cells without adverse effects in normal prostate epithelial cells

2006

Self Cite

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“…1 and references therein). Conversely, we and others have demonstrated that whereas HDACi induce expression of death receptors, ligands, and down-regulate inhibitors of death-receptor signaling such as cellular c-FLIP (7) and XIAP (8), the intrinsic rather than the extrinsic pathway is necessary for HDACi-mediated apoptosis (1). We therefore propose that there is a mechanistic rationale for combining HDACi with death receptor stimuli-either the HDACi will augment death receptor-mediated apoptosis by hyperactivating the same pathway, or the simultaneous activation of the extrinsic and intrinsic apoptotic pathways will result in additive or synergistic killing.…”

mentioning

confidence: 99%

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Frew

Lindemann

Martin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

128

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Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.

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“…Decreased cFLIP expression following RNA interference has also been shown to significantly enhance cell death in TRAILtreated cancer cells [30,62], including ovarian cancer cells [33]. Decreased cFLIP expression following treatment with other agents, including the chemotherapeutic agents actinomycin D, doxorubicin and CDDP [63], histone deacetylase inhibitors [64], and trichostatin A [65] may also contribute to increased TRAIL sensitivity, although in many cases these agents also induce pro-apoptotic changes in the expression of other molecules associated with apoptosis. Decreased cFLIP expression following reovirus infection in combination with TRAIL thus represents a new treatment strategy which has potential for the treatment of many human cancers.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

Clarke

Tyler

2006

Apoptosis

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Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) shows promise as a chemotherapeutic agent. However, many human cancer cells are resistant to killing by TRAIL. We have previously demonstrated that reovirus infection increases the susceptibility of human lung (H157) and breast (ZR75-1) cancer cell lines to TRAIL-induced apoptosis. We now show that reovirus also increases the susceptibility of human ovarian cancer cell lines (OVCAR3, PA-1 and SKOV-3) to TRAIL-induced apoptosis. Reovirus-induced increases in susceptibility of OVCAR3 cells to TRAIL require virus uncoating and involve increased activation of caspases 3 and 8. Reovirus infection results in the down-regulation of cFLIP (cellular FLICE inhibitory protein) in OVCAR3 cells. Down-regulation of cFLIP following treatment of OVCAR3 cells with antisense cFLIP oligonucleotides or PI3 kinase inhibition also increases the susceptibility of OVCAR3 cells to TRAIL-induced apoptosis. Finally, over-expression of cFLIP blocks reovirus-induced sensitization of OVCAR3 cells to TRAIL-induced apoptosis. The combination of reovirus and TRAIL thus represents a promising new therapeutic approach for the treatment of ovarian cancer.

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In vitro efficacy of AdTRAIL gene therapy of bladder cancer is enhanced by trichostatin A-mediated restoration of CAR expression and downregulation of cFLIP and Bcl-XL

Cited by 32 publications

References 34 publications

The histone deacetylase inhibitors depsipeptide and MS-275, enhance TRAIL gene therapy of LNCaP prostate cancer cells without adverse effects in normal prostate epithelial cells

The histone deacetylase inhibitors depsipeptide and MS-275, enhance TRAIL gene therapy of LNCaP prostate cancer cells without adverse effects in normal prostate epithelial cells

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

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