Concepts in in vivo siRNA delivery for cancer therapy

Gondi, Christopher S.; Rao, Jasti S.

doi:10.1002/jcp.21790

Cited by 69 publications

(53 citation statements)

References 90 publications

(71 reference statements)

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“…RNAi is in fact a natural process, and this is best exemplified by the discovery of naturally encoded structural hairpin RNA molecules that are called microRNAs (miRNAs), which are now known to play extremely important roles in regulating gene expression at the post-transcriptional level (13,14 …”

Section: Introductionmentioning

confidence: 99%

Silencing of the human TERT gene by RNAi inhibits A549 lung adenocarcinoma cell growth in vitro and in vivo

Xie

Chen

He³

et al. 2011

Oncol Rep

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Abstract. Human telomerase reverse transcriptase (hTERT) is the catalytic subunit and the activity determinant factor of the telomerase enzyme which maintains the length of human chromosomes. In recent years it has become an attractive molecular target for cancer gene therapy. In the present study, we show that hTERT siRNA effectively suppressed the expression of hTERT mRNA and hTERT protein levels, reduced telomerase activity, and induced apoptosis of A549 lung adenocarcinoma cells (P<0.05). In vivo, tumors treated with the hTERT siRNA were of reduced sizes, indicating that the hTERT siRNA also reduced the tumorigenic potential of lung adenocarcinoma cells (P<0.05). These results demonstrate that hTERT siRNA can cause effective suppression of telomerase and lead to apoptosis in A549 lung adenocarcinoma cells. hTERT siRNA may, therefore, be a strong candidate for highly selective therapy for chemoprevention and treatment of lung adenocarcinoma. IntroductionTelomerase, a ribonucleoprotein holoenzyme, maintains the length of telomeres which protect the chromosomes from DNA degradation, end-to-end fusions, rearrangements and chromosome loss at the ends of eukaryotic linear chromosomes. hTERT, the catalytic subunit of the telomerase complex, maintains the length of telomeres by reverse transcription and addition of TTAGGG repeats onto the telomeric ends of the chromosomes (1). The cellular activity of telomerase is determined by the presence or absence of hTERT and hTERT is the major determinant of telomerase activity (2). Human normal somatic cells have no telomerase activity. During each cell division, a portion of terminal DNA repeats may be lost with each cycle of DNA replication. When telomeres reach a critical length, the cells send out a signal to stop chromosome duplication and cellular division, and cellular senescence and apoptosis occur (3). But the majority of cancer cell lines and tumors have high telomerase activities, mainly by enhancing the expression of hTERT (4). Research shows a high expression of the hTERT gene in 90% malignant cancers, while low or undetectable levels in most normal tissue cells. Numerous studies have demonstrated that telomerase activity is present in almost all tumor samples (5), and our previous study has also shown that telomerase activity could be detected in 75% non-small cell lung cancer (NSCLC) specimens (6). Moreover, Tomlinson et al (7) found that the trafficking of hTR to both telomeres and Cajal bodies, where telomerase is active and is not observed in primary cells, depends on hTERT. Furthermore, telomerase seems to exert its anti-apoptotic effects via extratelomeric mitochondria and the caspase pathway (8,9). Therefore, inhibition of hTERT results in an inability of tumor cells to maintain telomeres and in loss of extratelomeric anti-apoptotic roles thus leading to tumor cell apoptosis. In recent years, hTERT has become an attractive molecular target for cancer therapy.Reverse transcriptase inhibitors, antisense oligonucleotides and RNA interference (RNAi) all indu...

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Section: Introductionmentioning

confidence: 99%

Silencing of the human TERT gene by RNAi inhibits A549 lung adenocarcinoma cell growth in vitro and in vivo

Xie

Chen

He³

et al. 2011

Oncol Rep

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“…In the majority of eukaryotes, RNAi is an evolutionarily conserved process that inhibits gene expression primarily by targeting mRNAs (12). To date, numerous studies have been conducted in a variety of animal models to investigate the efficacy of siRNAs as therapeutic agents; their findings indicate that specific siRNAs could inhibit the expression of target genes when administered locally or systemically (13,1�).…”

Section: Discussionmentioning

confidence: 99%

Silencing of c-kit with small interference RNA attenuates inflammation in a murine model of allergic asthma

Wang

Dong

et al. 2012

Int J Mol Med

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Abstract. A�� -A�� -ized by the inflammation of the airways due to infiltration and activation of several inflammatory cells that produce cytok��. �-kit, � ��-��g�� k�� receptor, has been found to be associated with allergic inflammation. The aim of the present study was to assess whether silencing of c-kit with small interference RNA (siRNA) would attenuate inflammation in allergic asthma. A mouse model of ovalbumin (OVA)-induced allergic asthma was treated with systemic administration of anti-c-kit siRNA to inhibit the expression of the c-kit gene. siRNAs were injected through the vena caudalis. We measured inflammatory response in both anti-c-kit siRNA-treated and control mice. Systemic administration of siRNA could effectively inhibit the expression of the c-kit gene and reduce the infiltration of inflammatory cells (eosinophils and lymphocytes) into the lung tissue and bronchoalveolar lavage fluid. In addition, we found that c-kit siRNA can decrease the production of the T-helper type 2 (Th2) cytokines, interleukin � (I�-�) and I�-�, but has no infl uinterleukin � (I�-�) and I�-�, but has no infl u-(I�-�) and I�-�, but has no influ-�� IFN-γ generation. These results show that inhibition of c-kit expression with siRNA can reduce the inflammatory response in allergic asthma.

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“…miRNAs exist stably in various tissues and structures, and therefore should be relatively easy to transport into cells via blood vessels and other structures (Mitchell et al, 2008). Transport methods for short interfering RNA (siRNA) should also be applicable to miRNA (Gondi and Rao, 2009;Broderick and Zamore, 2011) due to the structural similarity of miRNA and siRNA. Nanoparticles contribute to the stability of miRNAs (Kong et al, 2012) and liposome-polycation-hyaluronic acid (LPH) modified with a single-chain antibody fragment (scFv) has been used for transport of miRNAs and siRNAs into cancer cells, with resultant downregulation of target genes (c-Myc, MDM2 and VEGF).…”

Section: Application Of Mirna For Treat-ment Of Endometrial Cancermentioning

confidence: 99%

MicroRNAs in endometrial cancer

et al. 2013

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Endometrial cancer is a common malignant gynecological tumor, but there are few biomarkers that are useful for early and accurate diagnosis and few treatments other than surgery. However, use of microRNAs (miRNAs) that induces gene downregulation in cells may permit effective and minimally invasive diagnosis and treatment. In endometrial cancer cells, expression levels of miRNAs including miR-185, miR-210 and miR-423 are upregulated and those of miR-let7e, miR-30c and miR-221 are downregulated compared to normal tissues, and these miRNAs are involved in carcinogenesis, invasion and metastasis. miRNAs with expression changes such as miR-181b, miR-324-3p and miR-518b may be used as prognostic biomarkers and transfection of miR-152 may inhibit cancer growth. However, most current studies of miRNAs are at a basic level and further work is needed to establish clinical applications targeting miRNAs.

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Concepts in in vivo siRNA delivery for cancer therapy

Cited by 69 publications

References 90 publications

Silencing of the human TERT gene by RNAi inhibits A549 lung adenocarcinoma cell growth in vitro and in vivo

Silencing of the human TERT gene by RNAi inhibits A549 lung adenocarcinoma cell growth in vitro and in vivo

Silencing of c-kit with small interference RNA attenuates inflammation in a murine model of allergic asthma

MicroRNAs in endometrial cancer

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