Enhanced Inhibition of Tumorigenesis Using Combinations of miRNA-Targeted Therapeutics

Abstract

The search for effective strategies to inhibit tumorigenesis remains one of the most relevant scientific challenges. Among the most promising approaches is the direct modulation of the function of short non-coding RNAs, particularly miRNAs. These molecules are propitious targets for anticancer therapy, since they perform key regulatory roles in a variety of signaling cascades related to cell proliferation, apoptosis, migration, and invasion. The development of pathological states is often associated with deregulation of miRNA expression. The present review describes in detail the strategies aimed at modulating miRNA activity that invoke antisense oligonucleotide construction, such as small RNA zippers, miRNases (miRNA-targeted artificial ribonucleases), miRNA sponges, miRNA masks, anti-miRNA oligonucleotides, and synthetic miRNA mimics. The broad impact of developed miRNA-based therapeutics on the various events of tumorigenesis is also discussed. Above all, the focus of this review is to evaluate the results of the combined application of different miRNA-based agents and chemotherapeutic drugs for the inhibition of tumor development. Many studies indicate a considerable increase in the efficacy of anticancer therapy as a result of additive or synergistic effects of simultaneously applied therapies. Different drug combinations, such as a cocktail of antisense oligonucleotides or multipotent miRNA sponges directed at several oncogenic microRNAs belonging to the same/different miRNA families, a mixture of anti-miRNA oligonucleotides and cytostatic drugs, and a combination of synthetic miRNA mimics, have a more complex and profound effect on the various events of tumorigenesis as compared with treatment with a single miRNA-based agent or chemotherapeutic drug. These data provide strong evidence that the simultaneous application of several distinct strategies aimed at suppressing different cellular processes linked to tumorigenesis is a promising approach for cancer therapy.

The Effects of Combination of Mimic miR-155-5p and Antagonist miR-324-5p Encapsulated Chitosan in Ovarian Cancer SKOV3

“…Based on in silico research by Nurasih et al, (2018) miR-324-5p targeting GLI1 through Hedgehog signaling pathway. Miroshnichenko et al, (2019) demonstrated the success of miRNA-based therapy combined with chemotherapy drugs to inhibit tumor development. Recent studies have shown a considerable increase in the efficacy of anticancer therapy as a synergistic effect of the therapy being applied simultaneously.…”

Molecular mechanisms of epithelial to mesenchymal transition in tumor metastasis

“…Modulating of miRNA levels or restoring their function may be a new strategy in the cancer treatment. There are two ways to modulate the level of a particular miRNA: restoration of tumor suppressor miRNA by a straightforward transfection of synthetic mimics or transduction of cells with vectors expressing miRNAs (Miroshnichenko & Patutina, 2019). On the other hand, new technologies have been developed to inhibit functions of oncogenic miRNAs.…”

“…On the other hand, new technologies have been developed to inhibit functions of oncogenic miRNAs. Such compounds may target the miRNA sequence or interrupt the miRNA regulatory activity through interaction with their mRNA targets (Miroshnichenko & Patutina, 2019). Modulation of the miRNAs' level may be used to directly target tumor cells or it may also enhance other therapies, which has been shown in small cell lung cancer for miR-100 that regulated chemo-resistant properties of cancer cells (Xiao et al, 2014).…”

Up-Regulation of MiRNA-125a-5p Inhibits Cell Proliferation and Increases EGFR-TKI Induced Apoptosis in Lung Cancer Cells

“…MicroRNAs (miRNAs) are abundant class of non-coding 18-25 nucleotide small RNAs, which bind to the 3'-UTR of specific target mRNAs to suppress gene expression, either via inducing translational inhibition or mRNA degradation (Ricciuti et al, 2014;Abu-Duhier et al, 2018;Amri et al, 2019). MiRNAs participate in a variety of biological processes, such as cell cycle progression, proliferation, growth and apoptosis (Zhang et al, 2014;Fatima et al, 2019;Miroshnichenko and Patutina, 2019). Aberrant expression of particular miRNAs is a hallmark of many human tumor types, including NSCLC, and they can act as either oncogenes or as tumor suppressors (Zhao et al, 2013;MacDonagh et al, 2015;Yin et al, 2017;Bharali et al, 2018).…”