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.
Highlights
Tumorigenesis represents a complex process characterized by several hallmarks including fast, uncontrolled cell proliferation, reprogramming of energy metabolism, resistance to cell death and replicative senescence, immortalization, evasion of immune surveillance, abundant vascularization, infiltrated growth, and metastasis (Markopoulos et al, 2017)
Temozolomide, as an alkylating agent, promotes the initiation of apoptosis as a result of DNA damage during replication (Ohba and Hirose, 2016); sunitinib exhibits an anti-angiogenic effect by inhibiting tyrosine kinase receptors, in particular, the vascular endothelial growth factor receptor (Patel et al, 2016); gemcitabine, being a nucleotide analog bearing 2 -fluorine, blocks DNA synthesis (Song et al, 2016); cetuximab represents a monoclonal antibody that represses cell proliferation through the selective inhibition of the epidermal growth factor receptor (Li et al, 2015); and paclitaxel, belonging to the class of taxanes, exerts its cytostatic activity via suppression of the normal reorganization of microtubules during mitosis (Yardley, 2013)
A lack of sensitivity to several chemotherapeutics may be a consequence of the hyperfunction of oncogenic miRNAs such as miRNA-26a, miRNA-18a, miRNA-29b-1, miRNA-431, miRNA-4521, and miRNA-155, or may be the result of a significant decrease in the activity of tumor suppressor miRNAs, including miRNA-575, miRNA-642b, miRNA-4430, miRNA-203a, and miRNA-203b (Mikamori et al, 2017; Yamaguchi et al, 2017; Ge et al, 2018; Aako et al, 2019; Wang H. et al, 2019; Wang M. et al, 2019)
Summary
Tumorigenesis represents a complex process characterized by several hallmarks including fast, uncontrolled cell proliferation, reprogramming of energy metabolism, resistance to cell death and replicative senescence, immortalization, evasion of immune surveillance, abundant vascularization, infiltrated growth, and metastasis (Markopoulos et al, 2017). There is only one publication that demonstrates the in vivo application of an antisense oligonucleotide mix that consisted of anti-miRNA-221 and anti-miRNA-222 ONs, and provided only a 1.5-fold greater inhibition of tumor growth as compared with each ON used alone (Zhang et al, 2009; Supplementary Table S1).
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