Transformation by Retroviral Vectors of Bone Marrow-Derived Mesenchymal Cells Induces Mitochondria-Dependent cAMP-Sensitive Reactive Oxygen Species Production

Piccoli, Cláudia; Scrima, Rosella; Ripoli, Maria; Ianni, Mauro Di; Papa, Beatrice Del; D’Aprile, Annamaria; Quarato, Giovanni; Martelli, Maria Paola; Servillo, Giuseppe; Ligas, Claudio; Boffoli, Domenico; Tabilio, Antonio; Capitanio, Nazzareno

doi:10.1634/stemcells.2007-0885

Cited by 24 publications

(10 citation statements)

References 63 publications

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“…Piccoli et al (2008) demonstrated increased reactive oxygen species production in engineered BM-MSC due to regularly used selection markers. Expression of neomycin or puromycin resistance genes resulted in oxidative stress.…”

Section: Genetically Engineered Msc For Gene Directed Enzyme Prodrug mentioning

confidence: 99%

Mesenchymal stromal cells retrovirally transduced with prodrug-converting genes are suitable vehicles for cancer gene therapy

Durinikova¹,

Kučerová²,

Matúšková³

2014

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Summary. -Mesenchymal stem/stromal cells (MSC) possess a set of several fairly unique properties which make them ideally suitable both for cellular therapies and regenerative medicine. These include: relative ease of isolation, the ability to differentiate along mesenchymal and non-mesenchymal lineages in vitro and the ability to be extensively expanded in culture without a loss of differentiative capacity. MSC are not only hypoimmunogenic, but they mediate immunosuppression upon transplantation, and possess pronounced anti-inflammatory properties. They are able to home to damaged tissues, tumors, and metastases following systemic administration. The ability of homing holds big promise for tumor-targeted delivery of therapeutic agents. Viruses are naturally evolved vehicles efficiently transferring their genes into host cells. This ability made them suitable for engineering vector systems for the delivery of genes of interest. MSC can be retrovirally transduced with genes encoding prodrug-converting genes (suicide genes), which are not toxic per se, but catalyze the formation of highly toxic metabolites following the application of a nontoxic prodrug. The homing ability of MSC holds advantages compared to virus vehicles which display many shortcomings in effective delivery of the therapeutic agents. Gene therapies mediated by viruses are limited by their restricted ability to track cancer cells infiltrating into the surrounding tissue, and by their low migratory capacity towards tumor. Thus combination of cellular therapy and gene delivery is an attractive option -it protects the vector from immune surveillance, and supports targeted delivery of a therapeutic gene/protein to the tumor site.Keywords: mesenchymal stromal cells; retroviral vectors; cancer gene therapy; prodrug-converting genes * Corresponding author: E-mail: miroslava.matuskova@savba.sk; phone: +421-2-593-27418. Abbreviations: 5-FC = 5-fluorocytosine; 5-FU = 5-fluorouracil; AT-MSC = adipose tissue-derived mesenchymal stromal/stem cells; CD = cytosine deaminase; CD::UPRT-MSC = MSC expressing cytosine deaminase::uracil phosphoribosyl transferase; GCV = ganciclovir; GCV-TP = ganciclovir triphosphate; GDEPT = gene directed enzyme prodrug therapy; HSVtk = Herpes simplex virus thymidine kinase; MLV = murine leukemia virus; MSC = mesenchymal stromal cells/mesenchymal stem cells; PNP = purine nucleoside phosphorylase; RCRV = replication competent retroviral vector; UPRT = uracil phosphoribosyl transferase

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Section: Genetically Engineered Msc For Gene Directed Enzyme Prodrug mentioning

confidence: 99%

Mesenchymal stromal cells retrovirally transduced with prodrug-converting genes are suitable vehicles for cancer gene therapy

Durinikova¹,

Kučerová²,

Matúšková³

2014

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“…One possibility for viral induced redox perturbations was suggested by Piccoli et al [14]. They suggested that the overexpression of the antibiotic selection genes, Neo-R and PAC for LXSN and pQCXIP respectively are responsible for a decrease in mitochondrial electron transport chain Complex I functionality, and the subsequent increase in ROS [14].…”

Section: Discussionmentioning

confidence: 99%

Retroviral-infection increases tumorigenic potential of MDA-MB-231 breast carcinoma cells by expanding an aldehyde dehydrogenase (ALDH1) positive stem-cell like population

et al. 2014

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Retroviral transformation has been associated with pro-proliferative oncogenic signaling in human cells. The current study demonstrates that transduction of human breast carcinoma cells (MDA-MB231) with LXSN and QCXIP retroviral vectors causes significant increases in growth rate, clonogenic fraction, and aldehyde dehydrogenase-1 positive cells (ALDH1+), which is associated with increased steady-state levels of cancer stem cell populations. Furthermore, this retroviral-induced enhancement of cancer cell growth in vitro was also accompanied by a significant increase in xenograft tumor growth rate in vivo. The retroviral induced increases in cancer cell growth rate were partially inhibited by treatment with 100 U/ml polyethylene glycol-conjugated-(PEG)-superoxide dismutase and/or PEG-catalase. These results show that retroviral infection of MDA-MB231 human breast cancer cells is capable of enhancing cell proliferation and cancer stem cell populations as well as suggesting that modulation of reactive oxygen species-induced pro-survival signaling pathways may be involved in these effects.

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“…The present study also showed decreased cAMP concentration in the kidney tissue after endotoxemia and it was preserved by an infusion of amrinone. An increased tissue cAMP level has been shown to protect against hypoxemia induced endothelial injury by preserving endothelial barrier function [5], to improve post-ischemic recovery in the liver and kidney [6,7], and to regulate mitochondrial function [28,29]. Increasing cAMP attenuates iNOS expression [30].…”

Section: Discussionmentioning

confidence: 99%

The role of phosphodiesterase 3 in endotoxin-induced acute kidney injury

et al. 2009

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BackgroundAcute kidney injury frequently accompanies sepsis. Endotoxin is known to reduce tissue levels of cAMP and low levels of cAMP have been associated with renal injury. We, therefore, hypothesized that endotoxin induced renal injury by activating phosphodiesterase 3 (PDE3) which metabolizes cAMP and that amrinone an inhibitor of PDE3 would prevent the renal injury.MethodsAnimals were divided into three groups (n = 7/group): 1) Control (0.9% NaCl infusion without LPS); 2) LPS (0.9% NaCl infusion with LPS); 3) Amrinone+LPS (Amrinone infusion with LPS). Either lipopolysaccharide (LPS) or vehicle was injected via the jugular vein and the rats followed for 3 hours. We explored the expression of PDE3 isoenzymes and the concentrations of cAMP in the tissue.ResultsThe PDE3B gene but not PDE3A was upregulated in the kidney of LPS group. Immunohistochemistry also showed that PDE3B was expressed in the distal tubule in the controls and LPS caused PDE3B expression in the proximal as well. However, PDE3A was not expressed in the kidney either in the control or LPS treated groups. Tissue level of cAMP was decreased after LPS and was associated with an increase in blood urea nitrogen, creatinine, ultrastructural proximal tubular changes, and expression of inducible nitric oxide synthase (iNOS) in the endotoxemic kidney. In septic animals the phosphodiesterase 3 inhibitor, amrinone, preserved the tissue cAMP level, renal structural changes, and attenuated the increased blood urea nitrogen, creatinine, and iNOS expression in the kidney.ConclusionThese findings suggest a significant role for PDE3B as an important mediator of LPS-induced acute kidney injury.

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Transformation by Retroviral Vectors of Bone Marrow-Derived Mesenchymal Cells Induces Mitochondria-Dependent cAMP-Sensitive Reactive Oxygen Species Production

Abstract: ABSTRACT

Cited by 24 publications

References 63 publications

Mesenchymal stromal cells retrovirally transduced with prodrug-converting genes are suitable vehicles for cancer gene therapy

Mesenchymal stromal cells retrovirally transduced with prodrug-converting genes are suitable vehicles for cancer gene therapy

Retroviral-infection increases tumorigenic potential of MDA-MB-231 breast carcinoma cells by expanding an aldehyde dehydrogenase (ALDH1) positive stem-cell like population

The role of phosphodiesterase 3 in endotoxin-induced acute kidney injury

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