Targeting transcription factors for therapeutic benefit

Brennan, Paul; Donev, Rossen; Hewamana, Saman

doi:10.1039/b801920g

Cited by 43 publications

(38 citation statements)

References 120 publications

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“…They are usually downstream of many cell stimuli and thus targeting them could potentially have a similar effect to targeting the molecules upstream. Targeting them could also result into a better disease response, as they are usually involved in controlling a number of cell processes (Brennan et al 2008). There are many hurdles that need to be overcome before targeting TFs can be a viable treatment option.…”

Section: Targeting Transcription Factors: a New Approach In Tumour Immentioning

confidence: 99%

“…Direct strategies include: (a) peptides that specifically block transcription factor dimerisation, (b) peptides that target specific TF DNA-binding sequences (c) or decoy oligonucleotides containing the TF specific response element sequence. These strategies are discussed in detail in Brennan et al (2008). Here we would like to discuss a few recent papers that used this strategy in the context of cancer immunotherapy and the complement system.…”

Section: Targeting Transcription Factors: a New Approach In Tumour Immentioning

confidence: 99%

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Complement in Cancer and Cancer Immunotherapy

Kolev

Towner

Donev

2011

Arch. Immunol. Ther. Exp.

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Recently, there has been an increase of interest in the use of biological or immune-based therapies for patients with malignancies. This has been informed by the deeper understanding of the crosstalk between the host immune system and malignant tumours, as well as the potential advantages of immunotherapy-high specificity and less toxicity compared to standard approaches. The particular emphasis of this article is on the role of the complement system in tumour growth and antibody-based cancer immunotherapy. The functional consequences from overexpression of complement regulators by tumours and the development of strategies for overcoming this are discussed in detail. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of cancer.

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Section: Targeting Transcription Factors: a New Approach In Tumour Immentioning

confidence: 99%

Section: Targeting Transcription Factors: a New Approach In Tumour Immentioning

confidence: 99%

Complement in Cancer and Cancer Immunotherapy

Kolev

Towner

Donev

2011

Arch. Immunol. Ther. Exp.

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“…As in other cancers, transcription factors involved in development play a key role in the transformation of normal progenitors into malignant neuroblastoma (3,8,10,12,17,27). In humans, the transcription factor CASZ1 (also known as Castor or Cas), which localizes to chromosome 1p36, has been shown to be frequently deleted in neuroblastoma as well as other types of cancers, such as oligodendroglioma and breast cancer (1).…”

mentioning

confidence: 99%

Characterization of Critical Domains within the Tumor Suppressor CASZ1 Required for Transcriptional Regulation and Growth Suppression

Virden

Thiele

Liu

2012

Molecular and Cellular Biology

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CASZ1 is a zinc finger (ZF) transcription factor that is critical for controlling the normal differentiation of subtypes of neural and cardiac muscle cells. In neuroblastoma tumors, loss of CASZ1 is associated with poor prognosis and restoration of CASZ1 function suppresses neuroblastoma tumorigenicity. However, the key domains by which CASZ1 transcription controls developmental processes and neuroblastoma tumorigenicity have yet to be elucidated. In this study, we show that loss of any one of ZF1 to ZF4 resulted in a 58 to 79% loss in transcriptional activity, as measured by induction of tyrosine hydroxylase promoter-luciferase activity, compared to that of wild-type (WT) CASZ1b. Mutation of ZF5 or deletion of the C-terminal sequence of amino acids (aa) 728 to 1166 (a truncation of 38% of the protein) does not significantly alter transcriptional function. A series of N-terminal truncations reveals a critical transcriptional activation domain at aa 31 to 185 and a nuclear localization signal at aa 23 to 29. Soft agar colony formation assays and xenograft studies show that WT CASZ1b is more active in suppressing neuroblastoma growth than CASZ1b with a ZF4 mutation or a deletion of aa 31 to 185. This study identifies key domains needed for CASZ1b to regulate gene transcription. Furthermore, we establish a link between loss of CASZ1b transcriptional activity and attenuation of CASZ1b-mediated inhibition of neuroblastoma growth and tumorigenicity.

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“…In this scenario, the gene therapy approaches as decoys could represent a promising tool for the regulation of specific sets of genes [8,9]. Decoys are short stretches of /12 $58.00+.00 double stranded DNA mimicking the binding site of transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Innovative Erythrocyte-based Carriers for Gene Delivery in Porcine Vascular Smooth Muscle Cells: Basis for Local Therapy to Prevent Restenosis

Lande

Cecchettini²,

Tedeschi³

et al. 2012

CHDDT

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Vascular restenosis is affecting 30-40% of patients treated by percutaneous coronary angioplasty (PTCA). The advent of stenting reduced but not abolished restenosis. The introduction of drug eluting stent (DES) further reduced restenosis, but impaired endothelization exposed to intracoronary thrombosis as late adverse event. It is widely accepted that the endothelial denudation and coronary wall damages expose Vascular Smooth Muscle Cells (VSMC) to multiple growth factors and plasma circulating agents thus activating migration and proliferative pathways leading to restenosis. Among the major players of this processes, phosphorylated Elk-1, forming the Elk-1/SRF transcription complex, controls the expression of a different set of genes responsible for cell proliferation. Therefore, it is feasible that gene-specific oligonucleotide therapy targeting VSMC migration and proliferation genes can be a promising therapeutic approach. While a plethora of vehicles is suitably working in static in vitro cultures, methods for in vivo delivery of oligonucleotides are still under investigation. Recently, we have patented a novel erythrocyte-based drug delivery system with high capability to fuse with targeted cells thus improving drug bioavailability at the site of action. Here, the potential of these engineered porcine erythrocytes to deliver a synthetic DNA Elk-1 decoy inside syngenic porcine VSMC was tested. The results of this study indicate that Elk-1 decoy is actually able to inhibit cell proliferation and migration of VSMC. Our data also suggest that erythrocyte-based carriers are more efficient in delivering these oligonucleotides in comparison to conventional vehicles. As a consequence, a lower dose of Elk-1 decoy, delivered by engineered erythrocytes, was sufficient to inhibit cell growth and migration. This approach represents the translational step to reach in vivo experiments in pigs after PTCA and/or stent implantation where oligonucleotide drugs will be site-specific administered by using erythrocyte-based carriers to prevent restenosis.

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Targeting transcription factors for therapeutic benefit

Cited by 43 publications

References 120 publications

Complement in Cancer and Cancer Immunotherapy

Complement in Cancer and Cancer Immunotherapy

Characterization of Critical Domains within the Tumor Suppressor CASZ1 Required for Transcriptional Regulation and Growth Suppression

Innovative Erythrocyte-based Carriers for Gene Delivery in Porcine Vascular Smooth Muscle Cells: Basis for Local Therapy to Prevent Restenosis

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