Resveratrol is an effective inducer of CArG-driven TNF-α gene therapy

Bickenbach, Kai; Veerapong, Jula; Shao, Michael Y.; Mauceri, Helena J.; Posner, Mitchell C.; Kron, Stephen J.; Weichselbaum, Ralph R.

doi:10.1038/sj.cgt.7701103

Cited by 33 publications

(24 citation statements)

References 21 publications

(25 reference statements)

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“…These results are similar to those observed by Lopez [23]. In addition, RT-PCR and western blot assays demonstrated that human FL mRNA and protein are expressed in bone marrow cells after 5-FU treatment.…”

Section: Discussionsupporting

confidence: 90%

“…A common feature of chemotherapeutic agents is the production of oxygen and other free radical species that lead to DNA damage, lipid peroxidation, protein modification and cellular death [14,15]. ROIs are generated by a number of widely used anticancer drugs including doxorubicin [16], cisplatin [17], cyclophosphamide [18], 5-fluorouracil (5-FU) [19], gemcitabine [20], paclitaxel [21], temozolomide [22] and resveratrol [23]. We hypothesized that ROI generating chemotherapeutic agents could induce production of hematopoietic growth factor in bone marrow stromal cells transfected with a vector encoding the CArG elements of the Egr-1 promoter ligated upstream of cDNA encoding Flt3 Ligand.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional control of Flt3 ligand targeted by fluorouracil-induced Egr-1 promoter in hematopoietic damage

Pei²,

Zhou

et al. 2009

J Biomed Sci

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BackgroundIonizing radiation (IR) activate the early growth response-1 (Egr-1) promoter by production of radical oxygen intermediates (ROIs). Egr-EF, an expression vector pCIneo containing Egr-1 promoter cloned upstream of the cDNA for Flt3 ligand, was used to treat hematopoietic damage. 5-fluorouracil, a commonly used chemotherapeutic agent, cause tumor cell death by producing DNA damage and generating ROIs. We therefore hypothesized that clinically employed chemotherapeutic agents that increase ROIs could also be employed to activate Egr-EF in a chemoinducible gene therapy strategy. The goal of this study was to explore the effect of Flt3 Ligand gene transcription regulated by fluorouracil-induced Egr-1 promoter on hematopoietic recovery.MethodsHuman Flt3 Ligand (FL) cDNA and enhanced green fluorescent protein (EGFP) cDNA were linked together with IRES and inserted into the expression vector pCI-neo under control of the Egr-1 promoter (Egr-EF). The vector was transfected into the HFCL human bone marrow stromal cell line, and these cells were exposed to 5-FU, a chemotherapeutic drug. Expression of FL by HFCL/EF cells after 5-FU treatment was determined with ELISA, western blot and RT-PCR assays. In addition, the effect of FL from HFCL/EF cell culture supernatants on growth of CD34+ cells from cord blood was also studied. HFCL/EF cells were injected into CB-17 combined immunodeficient (SCID) mice with B16 melanoma. 5-FU was given three days after injection of the HFCL/EF cells. In the recipient mice, white blood cell levels in peripheral blood and expression of EGFP and FL in human stromal cells were measured. Tumor volumes in tumor-bearing mice were also measured.Results5-FU treatment increased EGFP levels and secreted FL levels in HFCL/EF cells. Supernatants from HFCL/EF cell cultures treated with 5-FU increased CD34+ cell growth significantly. HFCL/EF exhibited an increase in the number of white blood cells after chemotherapy.ConclusionThe data presented here support the use of transcriptional control mediated by chemoinducible gene therapy to reduce hematopoietic injury associated with 5-FU.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Transcriptional control of Flt3 ligand targeted by fluorouracil-induced Egr-1 promoter in hematopoietic damage

Pei²,

Zhou

et al. 2009

J Biomed Sci

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“…A recent study demonstrated that resveratrol activated Ad.Egr.TNF in tumor xenografts, and increased the anti-tumor response in both human and rat models. Thus, the activation of TNF-α expression by resveratrol may extend the use of Ad.Egr.TNF [98]. …”

Section: Other Therapeutic Uses Of Egr1mentioning

confidence: 99%

Is EGR1 a Potential Target for Prostate Cancer Therapy?

2009

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Prostate cancer is a major cause of cancer-related death in American men, for which finding new therapeutic strategies remains a challenge. Early growth response-1 (EGR1) is a transcription factor involved in cell proliferation and in the regulation of apoptosis. Although it has long been considered a tumor suppressor, a wealth of new evidence shows that EGR1 promotes the progression of prostate cancer. This review addresses the paradoxes of EGR1 function. While EGR1 mediates apoptosis in response to stress and DNA damage by regulating a tumor suppressor network, it also promotes the proliferation of prostate cancer cells by a mechanism that is not fully understood. Thus, EGR1 might be targeted for prostate cancer therapy either by ectopic expression in combination with radiotherapy or chemotherapy, or by direct inhibition for systemic treatment. Possible strategies to antagonize EGR1 function in a therapeutic setting are discussed. KeywordsEGR1; oncogene; prostate cancer; transgenic mouse mode; tumor suppressor Prostate cancer is the most commonly diagnosed cancer in men and the second highest cause of cancer-related death among men in the USA. In 2007, there were an estimated 218,890 new cases of prostate cancer and an estimated 27,050 deaths [1]. Routine use of prostate-specific antigen (PSA) screening enables a better diagnosis, but is still deficient in two ways. First, the correlation between PSA levels and the presence of cancer is indirect, so the presence of cancer must be confirmed by biopsy. Second, current biopsy methodology is diagnostic but not prognostic. Consequently, prostate cancer patients with minimally invasive forms of cancer needlessly undergo an aggressive surgical procedure.The progression of the disease follows multiple steps, from benign hyperplasia to hormoneindependent metastatic disease. Unfortunately, approximately 90% of patients with advanced disease will develop bone metastases, which are associated with severe pain, loss of mobility and spinal cord compression. Other affected organs may include the liver, lungs and brain [2]. Despite extensive research efforts, little hope exists for patients with hormone-refractory

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“…Polyphenols such as resveratrol have apparent liabilities associated with their structures, including extremely poor compound stability in vivo. Further, the emerging role of resveratrol in SIRT1-independent activities (for example, activation of Egr-1 [163] and SIRT2 [70]), the questions regarding its potency as an activator [164], and its potential inhibition of SIRT1 under certain conditions [165] has sparked interest in the development of more specific and potent sirtuin activators [166]. In one of the most remarkable pharmacological studies to date, a group at Sirtris Pharmaceuticals Inc. described novel SIRT1 activators, structurally unrelated to resveratrol and 1000 times more potent [83].…”

Section: Discovery and Development Of Sirtuin Ligandsmentioning

confidence: 99%

Biological and Potential Therapeutic Roles of Sirtuin Deacetylases

Taylor

Maxwell

Lüthi-Carter

et al. 2008

Cell. Mol. Life Sci.

123

127

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Sirtuins comprise a unique class of nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylases that target multiple protein substrates to execute diverse biological functions. These enzymes are key regulators of clinically important cellular and organismal processes, including metabolism, cell division and aging. The desire to understand the important determinants of human health and lifespan has resulted in a firestorm of work on the seven mammalian sirtuins in less than a decade. The implication of sirtuins in medically important areas such as diabetes, cancer, cardiovascular dysfunction and neurodegenerative disease has further catapulted them to a prominent status as potential targets for nutritional and therapeutic development. Here, we present a review of published results on sirtuin biology and its relevance to human disease.

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Resveratrol is an effective inducer of CArG-driven TNF-α gene therapy

Cited by 33 publications

References 21 publications

Transcriptional control of Flt3 ligand targeted by fluorouracil-induced Egr-1 promoter in hematopoietic damage

Transcriptional control of Flt3 ligand targeted by fluorouracil-induced Egr-1 promoter in hematopoietic damage

Is EGR1 a Potential Target for Prostate Cancer Therapy?

Biological and Potential Therapeutic Roles of Sirtuin Deacetylases

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