Transcriptional regulation of inducible nitric oxide synthase gene therapy: targeting early stage and advanced prostate cancer

Coulter, Jonathan A.; Page, Norbert P.; Worthington, Jenny; Robson, Tracy; Hirst, David

doi:10.1002/jgm.1495

Cited by 28 publications

(23 citation statements)

References 51 publications

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“…Indeed, our observations were in agreement with previous studies on the internalization of RALA/plasmid DNA nanoparticles, which occurs rapidly and relies on both clathrin- and caveolin-dependent processes 1 . We have demonstrated previously that iNOS gene therapies delivered intratumorally produce an impressive therapeutic benefit9, 10, 11, 12, 19 and described reporter gene expression when the Luciferase gene was delivered systemically using RALA, 1 but this is the first description of systemic RALA-mediated therapeutic transgene delivery and the first description of systemically delivered iNOS for cancer gene therapy. Both iNOS gene therapy constructs provoked inhibition of clonogenicity in vitro.…”

Section: Discussionsupporting

confidence: 92%

“…We have previously employed numerous transcriptional targeting strategies. Utilization of the prostate-specific membrane antigen (PSMA) promoter elicited iNOS transgene expression in prostate cancer lines but not in colon or breast carcinoma lines 11 . We have also used inducible promoters to control iNOS expression.…”

Section: Discussionmentioning

confidence: 99%

“…As an alternative approach to achieving therapeutic levels of intra-tumoral ·NO, we,9, 10, 11, 12, 13, 14 and others15, 16, 17 have demonstrated the benefit of iNOS as a therapeutic transgene. Constitutive iNOS expression abolished clonogenicity in ZR-75-1 breast cancer cells 13 and sensitized to cisplatin in human cancer cell lines and murine RIF-1 xenografts 9 and in A549 models of human primary and metastatic lung cancer 17 .…”

Section: Introductionmentioning

confidence: 99%

“…The hOC promoter is activated by transcription factors such as Runx2 and Fra-2 , which are commonly overexpressed in cancers that metastasize to bone 18 . hOC- iNOS -derived ·NO achieved almost complete elimination of colony-forming ability in PC-3 and DU145 castration-resistant prostate cancer cells and induced stasis in PC-3 xenografts 11, 19…”

Section: Introductionmentioning

confidence: 99%

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Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

McCrudden

McBride

McCaffrey

et al. 2017

Molecular Therapy - Nucleic Acids

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This study aimed to determine the therapeutic benefit of a nanoparticular formulation for the delivery of inducible nitric oxide synthase (iNOS) gene therapy in a model of breast cancer metastasis. Nanoparticles comprising a cationic peptide vector, RALA, and plasmid DNA were formulated and characterized using a range of physiochemical analyses. Nanoparticles complexed using iNOS plasmids and RALA approximated 60 nm in diameter with a charge of 25 mV. A vector neutralization assay, performed to determine the immunogenicity of nanoparticles in immunocompetent C57BL/6 mice, revealed that no vector neutralization was evident. Nanoparticles harboring iNOS plasmids (constitutively active cytomegalovirus [CMV]-driven or transcriptionally regulated human osteocalcin [hOC]-driven) evoked iNOS protein expression and nitrite accumulation and impaired clonogenicity in the highly aggressive MDA-MB-231 human breast cancer model. Micrometastases of MDA-MB-231-luc-D3H1 cells were established in female BALB/c SCID mice by intracardiac delivery. Nanoparticulate RALA/CMV-iNOS or RALA/hOC-iNOS increased median survival in mice bearing micrometastases by 27% compared with controls and also provoked elevated blood nitrite levels. Additionally, iNOS gene therapy sensitized MDA-MB-231-luc-D3H1 tumors to docetaxel treatment. Studies demonstrated that systemically delivered RALA-iNOS nanoparticles have therapeutic potential for the treatment of metastatic breast cancer. Furthermore, detection of nitrite levels in the blood serves as a reliable biomarker of treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

McCrudden

McBride

McCaffrey

et al. 2017

Molecular Therapy - Nucleic Acids

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“…We have also shown that PEDF concomitantly reduces cell proliferation and up-regulates iNOS in highly metastatic prostate cancer cells (Filleur, personal unpublished data) implying that PEDF could regulate the expression of iNOS in various cell types. These data could be of interest as iNOS over-expression has been recently described as increasing cytotoxicity in androgen-dependent and -independent prostate cancer cell lines (53,54). iNOS gene therapy also enhances the toxicity of cisplatin in prostate cancer cells (55).…”

Section: Discussionmentioning

confidence: 90%

Positive correlation between PEDF expression levels and macrophage density in the human prostate

Nelius¹,

Samathanam²,

Martinez-Marin³

et al. 2012

The Prostate

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BACKGROUND In this study, we investigated the capacity of PEDF to modulate the recruitment and the differentiation of monocytes/macrophages both in vitro and in human prostate. METHODS Using Boyden chambers, we assessed PEDF effect on the migration of monocytes and chemically-activated RAW264.7 macrophages. Normal, prostatitis and prostate cancer specimens were retrospectively selected and examined by immunohistochemistry for PEDF expression and infiltration of immune CD68+macrophagic cells. PEDF expression and macrophage density were then correlated with each other and clinicopathological parameters. M1 and M2 differentiation markers were quantified by qRT-PCR, western blotting and ELISA. RESULTS In chemotaxis, PEDF induced the migration of monocytes/macrophages. In immunohistochemistry, macrophages were markedly increased in prostatitis and malignant compared to normal tissues. PEDF was expressed at variable levels in the stroma and epithelium. PEDF mRNA was down-regulated in both prostate cancer and prostatitis compared to normal tissues. In correlation studies, macrophage density and PEDF expression were respectively positively and negatively associated with prostate size. Most importantly, PEDF expression positively correlated with macrophage density. Finally, PEDF stimulated the expression of iNOS, IL12 and TNFα; and inhibited IL10 and arginase 1 in mouse and human macrophages confirming a M1-type differentiation. CONCLUSIONS Our data demonstrate that PEDF acts directly on monocytes/macrophages by inducing their migration and differentiation into M1-type cells. These findings suggest a possible role of macrophages in PEDF anti-tumor properties and may support further development of PEDF-based anti-cancer therapy.

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Cancer Gene Therapy by Tissue‐specific and Cancer‐targeting Promoters

Hsu

Huo

et al. 2014

Cancer Gene Therapy by Viral and Non‐viral Vectors

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Transcriptional regulation of inducible nitric oxide synthase gene therapy: targeting early stage and advanced prostate cancer

Cited by 28 publications

References 51 publications

Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

Positive correlation between PEDF expression levels and macrophage density in the human prostate

Cancer Gene Therapy by Tissue‐specific and Cancer‐targeting Promoters

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