Miroshnichenko Svetlana, Patutina Olga
Laboratory of Nucleic Acids Biochemistry, Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.
Front Pharmacol. 2019 May 16;10:488. doi: 10.3389/fphar.2019.00488. eCollection 2019.
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.
寻找抑制肿瘤发生的有效策略仍然是最具相关性的科学挑战之一。最有前景的方法之一是直接调节短非编码RNA（特别是miRNA）的功能。这些分子是抗癌治疗的有利靶点，因为它们在与细胞增殖、凋亡、迁移和侵袭相关的各种信号级联反应中发挥关键调节作用。病理状态的发展通常与miRNA表达失调有关。本综述详细描述了旨在调节miRNA活性的策略，这些策略涉及反义寡核苷酸构建，如小RNA拉链、miRNase（靶向miRNA的人工核糖核酸酶）、miRNA海绵、miRNA掩码、抗miRNA寡核苷酸和合成miRNA模拟物。还讨论了基于miRNA的已开发疗法对肿瘤发生的各种事件的广泛影响。最重要的是，本综述的重点是评估不同的基于miRNA的药物与化疗药物联合应用抑制肿瘤发展的结果。许多研究表明，由于同时应用的疗法具有相加或协同作用，抗癌治疗的疗效显著提高。与单一的基于miRNA的药物或化疗药物治疗相比，不同的药物组合，如针对属于相同/不同miRNA家族的几种致癌微小RNA的反义寡核苷酸鸡尾酒或多能miRNA海绵、抗miRNA寡核苷酸和细胞抑制药物的混合物，以及合成miRNA模拟物的组合，对肿瘤发生的各种事件具有更复杂和深远的影响。这些数据提供了强有力的证据，即同时应用几种旨在抑制与肿瘤发生相关的不同细胞过程的不同策略是一种有前景的癌症治疗方法。
