Potential clinical applications of siRNA technique: benefits and limitations

Chen, Shaohua; Zhaori, Getu

doi:10.1111/j.1365-2362.2010.02400.x

Cited by 94 publications

(64 citation statements)

References 52 publications

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“…Previous preclinical studies validating Livin as therapeutic targets in gliomas have utilized Livin siRNA (33). However, it is not feasible to use the siRNA employed because of off-target effects, stimulation of the innate immune response, and inefficient delivery to target organ (34). Besides, a series of Smac mimetic peptides or compounds derived from the N-terminal tetrapeptide of a mitochondrial protein called Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with low pI) were designed as IAP antagonists (35).…”

Section: Discussionmentioning

confidence: 99%

Livin Contributes to Tumor Hypoxia–Induced Resistance to Cytotoxic Therapies in Glioblastoma Multiforme

Hsieh

Lin

et al. 2015

Clinical Cancer Research

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Purpose: Tumor hypoxia is one of the crucial microenvironments to promote therapy resistance (TR) in glioblastoma multiforme (GBM). Livin, a member of the family of inhibitor of apoptosis proteins, contributes antiapoptosis. However, the role of tumor hypoxia in Livin regulation and its impact on TR are unclear.Experimental Design: Livin expression and apoptosis for tumor hypoxic cells derived from human glioblastoma xenografts or in vitro hypoxic stress-treated glioblastoma cells were determined by Western blotting, immunofluorescence imaging, and annexin V staining assay. The mechanism of hypoxia-induced Livin induction was investigated by chromatin immunoprecipitation assay and reporter assay. Genetic and pharmacologic manipulation of Livin was utilized to investigate the role of Livin on tumor hypoxia-induced TR in vitro or in vivo.Results: The upregulation of Livin expression and downregulation of caspase activity were observed under cycling and chronic hypoxia in glioblastoma cells and xenografts, concomitant with increased TR to ionizing radiation and temozolomide. However, knockdown of Livin inhibited these effects. Moreover, hypoxia activated Livin transcription through the binding of hypoxiainducible factor-1a to the Livin promoter. The targeted inhibition of Livin by the cell-permeable peptide (TAT-Lp15) in intracerebral glioblastoma-bearing mice demonstrated a synergistic suppression of tumor growth and increased the survival rate in standardof-care treatment with radiation plus temozolomide.Conclusions: These findings indicate a novel pathway that links upregulation of Livin to tumor hypoxia-induced TR in GBM and suggest that targeting Livin using cell-permeable peptide may be an effective therapeutic strategy for tumor microenvironmentinduced TR.

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Section: Discussionmentioning

confidence: 99%

Livin Contributes to Tumor Hypoxia–Induced Resistance to Cytotoxic Therapies in Glioblastoma Multiforme

Hsieh

Lin

et al. 2015

Clinical Cancer Research

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“…9,43,44 In addition, because miRNAs may work as both tumor suppressors and oncogenes, these molecules could also be investigated as therapeutic targets, in that they could be knocked down when expressed in excess or replaced in cells when they have been pathologically reduced or lost. 45 Deregulated miRNA could also serve as a helpful biomarker for diagnosis and monitoring of disease.…”

Section: Rnai and Cancer: Therapeutic Implicationsmentioning

confidence: 99%

“…43,157,158,162 Various clinical trials are in progress, involving many companies. 163 We were able to find further as yet unpublished clinical trials registered at http://www.…”

Section: Ongoing Clinical Trials Of Sirna In Cancermentioning

confidence: 99%

“…One of the major likely benefits of the RNAi technique in the treatment of cancer is the feasibility of developing combination therapeutic RNAi approaches to inhibit multiple oncogenes or genes of proteins involved in tumorigenesis. 43 A correct approach could involve hitting multiple pathways simultaneously and/ or combining gene silencing with other therapies.…”

Section: Rnai and Cancer: Therapeutic Implicationsmentioning

confidence: 99%

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Nanoparticle-based delivery of small interfering RNA: challenges for cancer therapy

Gulino¹

2012

IJN

118

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During recent decades there have been remarkable advances and profound changes in cancer therapy. Many therapeutic strategies learned at the bench, including monoclonal antibodies and small molecule inhibitors, have been used at the bedside, leading to important successes. One of the most important advances in biology has been the discovery that small interfering RNA (siRNA) is able to regulate the expression of genes, by a phenomenon known as RNA interference (RNAi). RNAi is one of the most rapidly growing fields of research in biology and therapeutics. Much research effort has gone into the application of this new discovery in the treatment of various diseases, including cancer. However, even though these molecules may have potential and strong utility, some limitations make their clinical application difficult, including delivery problems, side effects due to off-target actions, disturbance of physiological functions of the cellular machinery involved in gene silencing, and induction of the innate immune response. Many researchers have attempted to overcome these limitations and to improve the safety of potential RNAi-based therapeutics. Nanoparticles, which are nanostructured entities with tunable size, shape, and surface, as well as biological behavior, provide an ideal opportunity to modify current treatment regimens in a substantial way. These nanoparticles could be designed to surmount one or more of the barriers encountered by siRNA. Nanoparticle drug formulations afford the chance to improve drug bioavailability, exploiting superior tissue permeability, payload protection, and the "stealth" features of these entities. The main aims of this review are: to explain the siRNA mechanism with regard to potential applications in siRNA-based cancer therapy; to discuss the possible usefulness of nanoparticlebased delivery of certain molecules for overcoming present therapeutic limitations; to review the ongoing relevant clinical research with its pitfalls and promises; and to evaluate critically future perspectives and challenges in siRNA-based cancer therapy.

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“…1) Synthetic small interfering RNA (siRNA) has been widely used for gene silencing in scientific research and is expected to become a beneficial drug for various diseases. [2][3][4] Although siRNA shows efficient gene silencing, the use of it is quite limited in vivo, especially for systemic usage, because of the rapid degradation of RNA in the bloodstream by nucleases, difficulty in delivery of it to target tissues, and its poor entry into the cytosol of target cells. 4) Therefore, establishment of a systemic siRNA delivery system that enables prolonged circulation without degradation by nucleases, active targeted delivery to the target tissue, and efficient entry of the siRNA into the target cells has been awaited.…”

mentioning

confidence: 99%

Systemic Delivery of Small Interfering RNA by Use of Targeted Polycation Liposomes for Cancer Therapy

Kenjo

Asai

Yonenaga

et al. 2013

Biological & Pharmaceutical Bulletin

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Novel polycation liposomes decorated with cyclic(Cys-Arg-Gly-Asp-d-Phe) peptide (cyclicRGD)-polyethylene glycol (PEG) (RGD-PEG-polycation liposomes (PCL)) were previously developed for cancer therapy based on RNA interference. Here, we demonstrate the in vivo delivery of small interfering RNA (siRNA) to tumors by use of RGD-PEG-PCL in B16F10 melanoma-bearing mice. Pharmacokinetic data obtained by positron emission tomography showed that cholesterol-conjugated siRNA formulated in RGD-PEG-PCL markedly accumulated in the tumors. Delivered by RGD-PEG-PCL, a therapeutic cocktail of siRNAs composed of cholesterol-conjugated siRNAs for c-myc, MDM2, and vascular endothelial growth factor (VEGF) were able to significantly inhibit the growth of B16F10 melanoma both in vitro and in vivo. These data suggest that targeted delivery of siRNAs by use of RGD-PEG-PCL has considerable potential for cancer treatment.

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Potential clinical applications of siRNA technique: benefits and limitations

Cited by 94 publications

References 52 publications

Livin Contributes to Tumor Hypoxia–Induced Resistance to Cytotoxic Therapies in Glioblastoma Multiforme

Livin Contributes to Tumor Hypoxia–Induced Resistance to Cytotoxic Therapies in Glioblastoma Multiforme

Nanoparticle-based delivery of small interfering RNA: challenges for cancer therapy

Systemic Delivery of Small Interfering RNA by Use of Targeted Polycation Liposomes for Cancer Therapy

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