Multi-modal effects of 1B3, a novel synthetic miR-193a-3p mimic, support strong potential for therapeutic intervention in oncology

Abstract

Compelling evidence demonstrates that miR-193a-3p is a tumor suppressor microRNA in many cancer types, and its reduced expression is linked to cancer initiation and progression, metastasis, and therapy resistance. However, its mechanism of action is not consistently described between studies, and often contradicts the pleiotropic role of a microRNA in manipulating several different mRNA targets. We therefore comprehensively investigated miRNA-193a-3p's mode of action in a panel of human cancer cell lines, with a variety of genetic backgrounds, using 1B3, a synthetic microRNA mimic. Interestingly, the exact mechanism through which 1B3 reduced cell proliferation varied between cell lines. 1B3 efficiently reduced target gene expression, leading to reduced cell proliferation/survival, cell cycle arrest, induction of apoptosis, increased cell senescence, DNA damage, and inhibition of migration. SiRNA silencing of 1B3 target mRNAs further highlighted the advantage of the pleiotropic mechanism of 1B3 action, as repression of individual targets did not achieve the same robust effect on cell proliferation in all cell lines. Importantly, a novel lipid nanoparticle-based formulation of 1B3, INT-1B3, demonstrated marked anti-tumor activity as a single agent following systemic administration in tumor-bearing mice. Together, these data strongly support the development of 1B3 as a novel therapeutic agent for treatment of human cancer.

Nanoparticle delivery of miR-21-3p sensitizes melanoma to anti-PD-1 immunotherapy by promoting ferroptosis

“…[66][67][68][69][70][71] Of note, AuNp is characterized by chemical inertness, biocompatibility, convenience in preparation and relative high cellular uptake efficiency, 72 73 and accumulative clinical trials revealed that miRNAs-based mimic drugs carried by multiple carriers had potent antitumor capacity with high specificity targeting tumor cells and some patients receiving these treatments gained encouraging response (NCT04675996). [23][24][25] Our data proved that systemic delivery of miR-21-3 p by AuNp could robustly increase the level of miR-21-3 p in transplanted tumors. More importantly, we also confirmed the low toxicity of miR-21-3 p-AuNp with the steady state in the number of blood cells and the maintenance of the physiological structure of multiple crucial organs after systemic administration.…”

“…[19][20][21][22] Moreover, some clinical trials reveal that miRNAs-based mimic drugs have potent antitumor capacity and a subset of patients can gain encouraging responses (NCT04675996 and NCT02369198). [23][24][25][26] Therefore, the employment of nanoparticle-based delivery of candidate miRNAs in the regulation of ferroptosis might be a promising synergistic approach for cancer immunotherapy, but the roles of miRNAs in anti-PD-1 immunotherapy-associated ferroptosis, as well as their therapeutic effect on melanoma, should be thoroughly investigated.…”

Cell cycle associated miRNAs as target and therapeutics in lung cancer treatment

“…MiR-138-5p has been found as the only miRNA regulating CDK8 in suppressing NSCLC [ 99 ]. In terms of Cyclins being regulated, Cyclin D1 was found to be regulated the most as miR-202, miR-206, miR-15, miR-9-5p, miR-15a, miR-16-5p, miR-193a-3p, miR-193b, miR-186, miR-545 and miR-146a-5p have been demonstrated impacting Cyclin D1 in their tumor suppression mechanism of lung cancers [ 7 , 89 , 93 , 100 , 101 , 102 , 103 , 104 ].…”

“…miRNAs and these cell cycle associated regulators interact in such a way that miRNAs control the expression of cell cycle regulators as either oncogenic or tumor suppressor miRNAs. Additionally, miRNAs can effectively suppress target genes while concurrently regulating a large number of genes of interest, which contributes to the treatment of cancer as a heterogeneous illness [ 7 ]. As a result, the identification and validation of effective role of miRNAs in cell cycle progression resulted in the emergence of novel treatment options for all forms of cancer progression.…”

Clinical progress of nanomedicine-based RNA therapies

“…This miRNA inhibits expression of the cyclin D1 protein, which is involved in tumor progression. This inhibition can induce tumor cell apoptosis and inhibit cell migration and proliferation in advanced solid tumors found in the colon, liver, skin, pancreatic, and breast cancer [ 64 ]. The addition of 2′-O-methyl nucleotide on the passenger strand of this miRNA mimic enabled it to impede inflammatory pathway activation and reduce adverse side effects, as well as increase binding efficacy of the miRNA strand to cyclin D1 mRNA in vivo [ 64 ].…”