Inhibition of Cell Proliferation by an Anti-EGFR Aptamer

Li, Na; Nguyen, Hong Hanh; Byrom, Michelle; Ellington, Andrew D.

doi:10.1371/journal.pone.0020299

Cited by 160 publications

(138 citation statements)

References 49 publications

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“…36 As seen in Figure 3G, SurR9-C84A exhibited proliferation inhibition in undifferentiated PCNA was expressed at the G 2 /M phase of the cell cycle, while Ki67 was expressed at all active phases of cell division except at the resting phase (G 0 ). 37 Therefore, these are both excellent markers for determining proliferation in differentiated SK-N-SH cells.…”

Section: Cell-proliferation Studymentioning

confidence: 80%

Nanoformulated cell-penetrating survivin mutant and its dual actions

Sriramoju¹,

Kanwar²,

Kanwar³

2014

IJN

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In this study, we investigated the differential actions of a dominant-negative survivin mutant (SurR9-C84A) against cancerous SK-N-SH neuroblastoma cell lines and differentiated SK-N-SH neurons. In both the cases, the mutant protein displayed dual actions, where its effects were cytotoxic toward cancerous cells and proliferative toward the differentiated neurons. This can be explained by the fact that tumorous (undifferentiated SK-N-SH) cells have a high endogenous survivin pool and upon treatment with mutant SuR9-C84A causes forceful survivin expression. These events significantly lowered the microtubule dynamics and stability, eventually leading to apoptosis. In the case of differentiated SK-N-SH neurons that express negligible levels of wild-type survivin, the mutant indistinguishably behaved in a wild-type fashion. It also favored cell-cycle progression, forming the chromosome-passenger complex, and stabilized the microtubule-organizing center. Therefore, mutant SurR9-C84A represents a novel therapeutic with its dual actions (cytotoxic toward tumor cells and protective and proliferative toward neuronal cells), and hence finds potential applications against a variety of neurological disorders. In this study, we also developed a novel poly(lactic- co -glycolic acid) nanoparticulate formulation to surmount the hurdles associated with the delivery of SurR9-C84A, thus enhancing its effective therapeutic outcome.

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Section: Cell-proliferation Studymentioning

confidence: 80%

Nanoformulated cell-penetrating survivin mutant and its dual actions

Sriramoju¹,

Kanwar²,

Kanwar³

2014

IJN

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“…Recently, our lab and others have generated aptamers that recognize a limited number of other cell surface receptors (Dollins et al, 2008a;Li et al, 2011) and have demonstrated that such aptamers can be internalized into cells and carry cargoes into them. Therefore this approach holds much promise for therapeutic development but unfortunately its utility is still hindered by significant limitations (Dollins et al, 2008b;Tiemann and Rossi, 2009;Zhou and Rossi, 2010).…”

Section: Introductionmentioning

confidence: 99%

Aptamer-Mediated Delivery of Splice-Switching Oligonucleotides to the Nuclei of Cancer Cells

Kotula

Pratico

Xin

et al. 2012

Nucleic Acid Therapeutics

100

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To reduce the adverse effects of cancer therapies and increase their efficacy, new delivery agents that specifically target cancer cells are needed. We and others have shown that aptamers can selectively deliver therapeutic oligonucleotides to the endosome and cytoplasm of cancer cells that express a particular cell surface receptor. Identifying a single aptamer that can internalize into many different cancer cell-types would increase the utility of aptamer-mediated delivery of therapeutic agents. We investigated the ability of the nucleolin aptamer (AS1411) to internalize into multiple cancer cell types and observed that it internalizes into a wide variety of cancer cells and migrates to the nucleus. To determine if the aptamer could be utilized to deliver therapeutic oligonucleotides to modulate events in the nucleus, we evaluated the ability of the aptamer to deliver splice-switching oligonucleotides. We observed that aptamer-splice-switching oligonucleotide chimeras can alter splicing in the nuclei of treated cells and are effective at lower doses than the splice switching oligonucleotides alone. Our results suggest that aptamers can be utilized to deliver oligonucleotides to the nucleus of a wide variety of cancer cells to modulate nuclear events such as RNA splicing.

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“…So far, several anti-ErbB-specific aptamers have been developed (10)(11)(12)(13)(14). They generally show high affinity and specificity to their targets and, in the case of ErbB-1-and ErbB-3-specific aptamers, they also inhibit the proliferation of cultured cancer cells (10,14). Notably, an aptamer against ErbB-1/EGFR was able to inhibit tumor growth in a mouse model (12), and ErbB-2-specific aptamers were used to deliver siRNAs targeting B-cell lymphoma 2 (Bcl-2) (15).…”

mentioning

confidence: 99%

Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth

Mahlknecht

Maron²,

Mancini

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

138

142

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Aptamers, oligonucleotides able to avidly bind cellular targets, are emerging as promising therapeutic agents, analogous to monoclonal antibodies. We selected from a DNA library an aptamer specifically recognizing human epidermal growth factor receptor 2 (ErbB-2/HER2), a receptor tyrosine kinase, which is overexpressed in a variety of human cancers, including breast and gastric tumors. Treatment of human gastric cancer cells with a trimeric version (42 nucleotides) of the selected aptamer (14 nucleotides) resulted in reduced cell growth in vitro, but a monomeric version was ineffective. Likewise, when treated with the trimeric aptamer, animals bearing tumor xenografts of human gastric origin reflected reduced rates of tumor growth. The antitumor effect of the aptamer was nearly twofold stronger than that of a monoclonal anti-ErbB-2/HER2 antibody. Consistent with aptamer-induced intracellular degradation of ErbB-2/HER2, incubation of gastric cancer cells with the trimeric aptamer promoted translocation of ErbB-2/HER2 from the cell surface to cytoplasmic puncta. This translocation was associated with a lysosomal hydrolase-dependent clearance of the ErbB-2/HER2 protein from cell extracts. We conclude that targeting ErbB-2/HER2 with DNA aptamers might retard the tumorigenic growth of gastric cancer by means of accelerating lysosomal degradation of the oncoprotein. This work exemplifies the potential pharmacological utility of aptamers directed at cell surface proteins, and it highlights an endocytosis-mediated mechanism of tumor inhibition.T he epidermal growth factor related protein (ErbB) family of receptor tyrosine kinases plays an important role in epitheliogenesis and, accordingly, serves as a major therapeutic target in several cancers. The family comprises four transmembrane receptors and 11 ligands that induce homodimerization or heterodimerization upon binding to the respective receptor (1). ErbB-1 (also called the epidermal growth factor receptor; EGFR) and ErbB-4 share some ligands, whereas no similar ligand is so far known for ErbB-2. Overexpression and mutations of ErbB family members lead to a multitude of malignancies. To date, synthetic tyrosine kinase inhibitors (e.g., Erlotinib and Gefitinib), as well as monoclonal antibodies (mAbs; e.g., Cetuximab and Trastuzumab), have been developed to inhibit pathological signaling or recruit the immune system to cancer cells (2). Aptamers might represent an alternative therapeutic modality. These molecules are small, singlestranded DNA or RNA molecules (3). RNA aptamers were described for the first time in 1990 by two laboratories (4, 5). Since then, aptamers against a multitude of different organic and inorganic, small and macromolecular, targets were developed. In addition, high-affinity aptamer binding ranging from picomolar to low nanomolar concentrations have been documented (6). Aptamers are selected in an evolutionary process called systematic evolution of ligands by exponential enrichment (SELEX). A DNA or RNA library containing single-stranded random ...

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Inhibition of Cell Proliferation by an Anti-EGFR Aptamer

Cited by 160 publications

References 49 publications

Nanoformulated cell-penetrating survivin mutant and its dual actions

Nanoformulated cell-penetrating survivin mutant and its dual actions

Aptamer-Mediated Delivery of Splice-Switching Oligonucleotides to the Nuclei of Cancer Cells

Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth

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