Current Status and Perspectives Regarding LNA‐Anti‐miR Oligonucleotides and microRNA miR‐21 Inhibitors as a Potential Therapeutic Option in Treatment of Colorectal Cancer

Avan, Amir; Ahmadian, Mehdi; Nia, Sasan Nedaee; Ranjbar, Maryam; Sharifi, Mohammadreza; Goli, Mohammad; Piroozmand, Ahmad; Nourmohammadi, Esmail; Manian, Mostafa; Ferns, Gordon A.; Ghayour‐Mobarhan, Majid; Salehi, Roya

doi:10.1002/jcb.26047

Cited by 28 publications

(14 citation statements)

References 151 publications

(173 reference statements)

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“…However despite the advances made in medical sciences over the last decade, drug resistance remains a principal reason for treatment failure ( 8 – 10 ). In colon cancer, patients develop drug resistance with the passage of treatment and ultimately stop responding to the available treatment options, which culminates in the failure of chemotherapy ( 11 , 12 ). Drug resistance is defined as a decrease in the effect of drugs, including chemotherapeutic agents or antibiotics, and targeting drug resistance, primarily multidrug resistance, remains one a major challenge ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin resistance induces IL6 activation in the colon cancer cell line LS180

Liao

Wang

et al. 2018

Oncol Lett

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Despite improvements in the development of drugs for the treatment of cancer, drug resistance remains a major obstacle. In colon cancer, following an initially promising response, patients develop drug resistance, which impacts the efficacy and halts the response of cancerous cells towards drugs. In the present study, a phosphatase and tensin homolog (PTEN) knockdown model of LS180 cells, doxorubicin-resistant models of LS180 cells as well as doxorubicin-resistant LS180 (PTEN) knockdown model were established. The present study demonstrated that doxorubicin resistance led to the activation of interleukin (IL)6 signalling pathway which was enhanced by knockdown of PTEN. There was also an increase in the levels of IL8 and IL2 which were further enchanced by knockdown of PTEN. Doxorubicin resistance also led to an increase in the population of cancer stem cells in LS180 and shPTEN-treated LS180 cells. Notably, doxorubicin resistance also induced epithelial to mesenchymal transition and increased the formation of mammospheres. Furthermore, the present study also reported that IL6 receptor antibody not only decreased IL6 levels but also led to a significant decreased number of cancer stem cell like population and mammosphere formation. In conclusion, in the present study it was demonstrated that doxorubicin resistance led to activation of IL6 signalling pathway which was further elevated by the knockdown of PTEN in the colon cancer cell line LS180. Thus, inhibiting the IL6 loop may provide an alternative pathway to tackle doxorubicin resistance.

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Section: Introductionmentioning

confidence: 99%

Doxorubicin resistance induces IL6 activation in the colon cancer cell line LS180

Liao

Wang

et al. 2018

Oncol Lett

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“…The LNAs chemical structure resides in an additional bridge that links both the 2′-oxygen and 4′-carbon positions of the ribose which locks the sugar at the 3′- endo conformation. This special feature has allowed LNA technology to be an important tool for antisense gene silencing processes and more recently in the search of miRNA-based therapeutics by designing efficient antagomiRs (LNA-antimiRs) for silencing miRNA expressions both in vitro and in vivo [ 185 , 186 ]. Important therapeutic results were achieved by Elmén et al who engineered a 15-mer oligonucleotide containing LNAs (>50%) which was entirely modified with phosphorothioate residues targeting miR-122 expression [ 187 ].…”

Section: Chemical Modifications and Mirna Deliverymentioning

confidence: 99%

Covalent Strategies for Targeting Messenger and Non-Coding RNAs: An Updated Review on siRNA, miRNA and antimiR Conjugates

Grijalvo

Alagia

Jorge

et al. 2018

Genes

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Oligonucleotide-based therapy has become an alternative to classical approaches in the search of novel therapeutics involving gene-related diseases. Several mechanisms have been described in which demonstrate the pivotal role of oligonucleotide for modulating gene expression. Antisense oligonucleotides (ASOs) and more recently siRNAs and miRNAs have made important contributions either in reducing aberrant protein levels by sequence-specific targeting messenger RNAs (mRNAs) or restoring the anomalous levels of non-coding RNAs (ncRNAs) that are involved in a good number of diseases including cancer. In addition to formulation approaches which have contributed to accelerate the presence of ASOs, siRNAs and miRNAs in clinical trials; the covalent linkage between non-viral vectors and nucleic acids has also added value and opened new perspectives to the development of promising nucleic acid-based therapeutics. This review article is mainly focused on the strategies carried out for covalently modifying siRNA and miRNA molecules. Examples involving cell-penetrating peptides (CPPs), carbohydrates, polymers, lipids and aptamers are discussed for the synthesis of siRNA conjugates whereas in the case of miRNA-based drugs, this review article makes special emphasis in using antagomiRs, locked nucleic acids (LNAs), peptide nucleic acids (PNAs) as well as nanoparticles. The biomedical applications of siRNA and miRNA conjugates are also discussed.

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“…It promotes adherence of monocytes via activator protein AP-1, as well as negatively regulating LPS-induced lipid accumulation and inflammatory responses in macrophages by the TLR4–NF-κB pathway ( Feng et al, 2014 ). The well-expressed and widespread miR-21 has in fact now been targeted in several other diseases too, including kidney disease, and cancer and trials of therapy are well underway ( Denby et al, 2014 ; Nedaeinia et al, 2017 ).…”

Section: Mirnasmentioning

confidence: 99%

Targeting Non-coding RNA in Vascular Biology and Disease

et al. 2018

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Only recently have we begun to appreciate the importance and complexity of the non-coding genome, owing in some part to truly significant advances in genomic technology such as RNA sequencing and genome-wide profiling studies. Previously thought to be non-functional transcriptional “noise,” non-coding RNAs (ncRNAs) are now known to play important roles in many diverse biological pathways, not least in vascular disease. While microRNAs (miRNA) are known to regulate protein-coding gene expression principally through mRNA degradation, long non-coding RNAs (lncRNAs) can activate and repress genes by a variety of mechanisms at both transcriptional and translational levels. These versatile molecules, with complex secondary structures, may interact with chromatin, proteins, and other RNA to form complexes with an array of functional consequences. A body of emerging evidence indicates that both classes of ncRNAs regulate multiple physiological and pathological processes in vascular physiology and disease. While dozens of miRNAs are now implicated and described in relative mechanistic depth, relatively fewer lncRNAs are well described. However, notable examples include ANRIL, SMILR, and SENCR in vascular smooth muscle cells; MALAT1 and GATA-6S in endothelial cells; and mitochondrial lncRNA LIPCAR as a powerful biomarker. Due to such ubiquitous involvement in pathology and well-known biogenesis and functional genetics, novel miRNA-based therapies and delivery methods are now in development, including some early stage clinical trials. Although lncRNAs may hold similar potential, much more needs to be understood about their relatively complex molecular behaviours before realistic translation into novel therapies. Here, we review the current understanding of the mechanism and function of ncRNA, focusing on miRNAs and lncRNAs in vascular disease and atherosclerosis. We discuss existing therapies and current delivery methods, emphasising the importance of miRNAs and lncRNAs as effectors and biomarkers in vascular pathology.

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Current Status and Perspectives Regarding LNA‐Anti‐miR Oligonucleotides and microRNA miR‐21 Inhibitors as a Potential Therapeutic Option in Treatment of Colorectal Cancer

Cited by 28 publications

References 151 publications

Doxorubicin resistance induces IL6 activation in the colon cancer cell line LS180

Doxorubicin resistance induces IL6 activation in the colon cancer cell line LS180

Covalent Strategies for Targeting Messenger and Non-Coding RNAs: An Updated Review on siRNA, miRNA and antimiR Conjugates

Targeting Non-coding RNA in Vascular Biology and Disease

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