scholarly journals Sulfonated Amphiphilic Poly(α)glutamate Amine—A Potential siRNA Nanocarrier for the Treatment of Both Chemo-Sensitive and Chemo-Resistant Glioblastoma Tumors

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2199
Author(s):  
Adva Krivitsky ◽  
Sabina Pozzi ◽  
Eilam Yeini ◽  
Sahar Israeli Dangoor ◽  
Tal Zur ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Interfering Rna ◽  
Dna Methyltransferase ◽  
Brain Targeting ◽  
Specific Gene ◽  
Brain Endothelial Cells ◽  
3 Dimensional ◽  
Methylguanine Dna Methyltransferase ◽  
Transmembrane Glycoprotein ◽  
Interfering Rna

Development of chemo-resistance is a major challenge in glioblastoma (GB) treatment. This phenomenon is often driven by increased activation of genes associated with DNA repair, such as the alkyl-removing enzyme O6-methylguanine-DNA methyltransferase (MGMT) in combination with overexpression of canonical genes related to cell proliferation and tumor progression, such as Polo-like kinase 1 (Plk1). Hereby, we attempt to sensitize resistant GB cells using our established amphiphilic poly(α)glutamate (APA): small interfering RNA (siRNA) polyplexes, targeting Plk1. Furthermore, we improved brain-targeting by decorating our nanocarrier with sulfonate groups. Our sulfonated nanocarrier showed superior selectivity towards P-selectin (SELP), a transmembrane glycoprotein overexpressed in GB and angiogenic brain endothelial cells. Self-assembled polyplexes of sulfonated APA and siPlk1 internalized into GB cells and into our unique 3-dimensional (3D) GB spheroids inducing specific gene silencing. Moreover, our RNAi nanotherapy efficiently reduced the cell viability of both chemo-sensitive and chemo-resistant GB cells. Our developed sulfonated amphiphilic poly(α)glutamate nanocarrier has the potential to target siRNA to GB brain tumors. Our findings may strengthen the therapeutic applications of siRNA for chemo-resistant GB tumors, or as a combination therapy for chemo-sensitive GB tumors.

scholarly journals RNA Interference of Human Papillomavirus Type 18 E6 and E7 Induces Senescence in HeLa Cells

2003 ◽  
Vol 77 (10) ◽  
pp. 6066-6069 ◽  
Author(s):  
Allison H. S. Hall ◽  
Kenneth A. Alexander
Keyword(s):  
Cell Proliferation ◽  
Human Papillomavirus ◽  
Rna Interference ◽  
Hela Cells ◽  
Tumor Suppressors ◽  
Small Interfering Rna ◽  
Promote Cell Proliferation ◽  
E6 And E7 ◽  
Cellular Dna ◽  
Interfering Rna

ABSTRACT The human papillomavirus oncoproteins E6 and E7 promote cell proliferation and contribute to carcinogenesis by interfering with the activities of cellular tumor suppressors. We used a small interfering RNA molecule targeting the E7 region of the bicistronic E6 and E7 mRNA to induce RNA interference, thereby reducing expression of E6 and E7 in HeLa cells. RNA interference of E6 and E7 also inhibited cellular DNA synthesis and induced morphological and biochemical changes characteristic of cellular senescence. These results demonstrate that reducing E6 and E7 expression is sufficient to cause HeLa cells to become senescent.

scholarly journals Lentivirus-delivered nemo-like kinase small interfering RNA inhibits laryngeal cancer cell proliferation in vitro

2015 ◽  
Vol 12 (4) ◽  
pp. 5619-5624
Author(s):  
JUN TAI ◽  
YUANSHENG RAO ◽  
JUGAO FANG ◽  
ZHIGANG HUANG ◽  
ZHENKUN YU ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Laryngeal Cancer ◽  
Small Interfering Rna ◽  
Cancer Cell Proliferation ◽  
Interfering Rna ◽  
Proliferation In Vitro

scholarly journals Antiviral Effects of Small Interfering RNA Simultaneously Inducing RNA Interference and Type 1 Interferon in Coxsackievirus Myocarditis

2012 ◽  
Vol 56 (7) ◽  
pp. 3516-3523 ◽  
Author(s):  
Jeonghyun Ahn ◽  
Ara Ko ◽  
Eun Jung Jun ◽  
Minah Won ◽  
Yoo Kyum Kim ◽  
...  
Keyword(s):  
Rna Interference ◽  
Small Interfering Rna ◽  
Antiviral Treatment ◽  
Coxsackievirus B3 ◽  
Hydroxyl Group ◽  
Specific Gene ◽  
Type I ◽  
Antiviral Effects ◽  
Direct Demonstration ◽  
Interfering Rna

ABSTRACTAntiviral therapeutics are currently unavailable for treatment of coxsackievirus B3, which can cause life-threatening myocarditis. A modified small interfering RNA (siRNA) containing 5′-triphosphate, 3p-siRNA, was shown to induce RNA interference and interferon activation. We aimed to develop a potent antiviral treatment using CVB3-specific 3p-siRNA and to understand its underlying mechanisms. Virus-specific 3p-siRNA was superior to both conventional virus-specific siRNA with an empty hydroxyl group at the 5′ end (OH-siRNA) and nonspecific 3p-siRNA in decreasing viral replication and subsequent cytotoxicity. A single administration of 3p-siRNA dramatically attenuated virus-associated pathological symptoms in mice with no signs of toxicity, and their body weights eventually reached the normal range. Myocardial inflammation and fibrosis were rare, and virus production was greatly reduced. A nonspecific 3p-siRNA showed relatively less protective effect under identical conditions, and a virus-specific OH-siRNA showed no protective effects. We confirmed that virus-specific 3p-siRNA simultaneously activated target-specific gene silencing and type I interferon signaling. We provide a clear proof of concept that coxsackievirus B3-specific 3p-siRNA has 2 distinct modes of action, which significantly enhance antiviral activities with minimal organ damage. This is the first direct demonstration of improved antiviral effects with an immunostimulatory virus-specific siRNA in coxsackievirus myocarditis, and this method could be applied to many virus-related diseases.

scholarly journals Unique Roles of p160 Coactivators for Regulation of Breast Cancer Cell Proliferation and Estrogen Receptor-α Transcriptional Activity

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1588-1596 ◽  
Author(s):  
Sudipan Karmakar ◽  
Estrella A. Foster ◽  
Carolyn L. Smith
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Small Interfering Rna ◽  
Breast Cancer Cells ◽  
Transcriptional Activity ◽  
Interfering Rna ◽  
Mcf 7

Each of the three members of the p160 steroid receptor coactivator (SRC) family of coactivators (SRC-1, SRC-2 and SRC-3) stimulates estrogen receptor (ER)-α function in trans-activation assays. Consequently, we sought to elucidate their contributions to the ER-regulated processes of cell proliferation, apoptosis, and the expression of ERα target genes in MCF-7 breast cancer cells. The small interfering RNA depletion of SRC-2 or SRC-3 but not SRC-1 inhibited growth of MCF-7 cells, and this was reflected in decreased cell cycle progression and increased apoptosis in SRC-2- or SRC-3-depleted cells as well as a reduction in ERα transcriptional activity measured on a synthetic reporter gene. However, only SRC-3 depletion blocked estradiol stimulated cell proliferation. Depletion of SRC-1 did not affect these events, and together this reveals functional differences between each of the three SRC family coactivators. Regulation of the endogenous ERα target gene, c-myc was not affected by depletion of any of the p160 coactivators although depletion of each of them decreased pS2 mRNA expression in estradiol-treated MCF-7 cells. Moreover, progesterone receptor and cyclin D1 gene expression were decreased in SRC-3 small interfering RNA-treated cells. Expression of mRNA and protein levels for the antiapoptotic gene, Bcl-2 was dependent on SRC-3 expression, whereas Bcl-2 protein but not mRNA expression also was sensitive to SRC-1 depletion. Together these data indicate that the closely related p160 coactivators are not functionally redundant in breast cancer cells because they play gene-specific roles in regulating mRNA and protein expression, and they therefore are likely to make unique contributions to breast tumorigenesis.

scholarly journals The G Protein-Coupled Receptor GPR30 Inhibits Human Urothelial Cell Proliferation

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 4024-4034 ◽  
Author(s):  
Jian Teng ◽  
Zun-Yi Wang ◽  
Eric R. Prossnitz ◽  
Dale E. Bjorling
Keyword(s):  
Cell Proliferation ◽  
Cyclin D1 ◽  
G Protein ◽  
Small Interfering Rna ◽  
Urothelial Cell ◽  
Urothelial Cells ◽  
G Protein Coupled Receptor ◽  
17Β Estradiol ◽  
Interfering Rna ◽  
G Protein Coupled

We have previously shown that estrogen stimulates cell proliferation in both normal and transformed urothelial cells mainly through activation of the two primary estrogen receptors (ERs), ERα and ERβ. A growing body of evidence suggests that estrogen also initiates nongenomic effects that cannot be explained by activation of primary ERs. In the present study, we observed that urothelial cells express high amounts of GPR30, a G protein-coupled receptor recently identified as a candidate for membrane-associated estrogen binding. Membrane- impermeable bovine serum albumin-conjugated 17β-estradiol and the specific GPR30 agonist G-1 both inhibited urothelial cell proliferation in a concentration-dependent manner. Transient overexpression of GPR30 inhibited 17β-estradiol (E2)-induced cell proliferation. Decreased GPR30 expression caused by specific small interfering RNA increased E2-induced cell proliferation. These results indicate that membrane-associated inhibitory effects of E2 on cell proliferation correlate with abundance of GPR30. Although E2 induced a significant increase in caspase-3/7 activity, G-1 did not, suggesting that the GPR30-mediated inhibitory effect on cell proliferation was not caused by apoptosis. Furthermore, we found that G-1 failed to induce c-fos, c-jun, and cyclin D1 expression, and GPR30 overexpression abolished E2-induced c-fos, c-jun, and cyclin D1 expression. However, inactivation of GPR30 by small interfering RNA increased c-fos, c-jun, and cyclin D1 expression. These results suggest that GPR30-mediated inhibition of urothelial cell proliferation is the result of decreased cyclin D1 by down-regulation of activation protein-1 signaling.

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