The silencing of microRNAs (miRNA/miRs) associated with acute lymphoblastic leukemia (ALL) demonstrated antileukemic effects in leukemic cell lines and appeared to enhance the effect of prednisolone treatment, according to the results of study published in BioMed Research International.
Although pediatric patients with ALL have high survival rates, relapse and drug resistance remain significant challenges. MiRNAs are important post-transcriptional regulators of gene expression that impact both physiological and pathological processes and represent potential therapeutic targets in ALL.
The investigators’ study was aimed to determine whether inhibition of miRNAs upregulated in leukemia, specifically miR-146a, miR-155, and miR-181a, with their corresponding anti-miRs, individually and in combination with prednisolone, would have anti-leukemic effects in leukemic cell lines (SUP-B15). B-lymphocyte cell lines without leukemia (NCI-BL 2171) and administration of anti-let-7e and let-7e, a miRNA involved in the proliferation of healthy hematopoietic stem cells, were also used in the study. The investigators measured cytotoxicity, cell proliferation, cell cycle, and apoptosis.
Across a total of 12 experimental groups, anti-miR treatment enhanced the cytotoxic effect of prednisolone on leukemia cells (viability percentage mean, 15.13%; max. value, 55.00%; min. value, 0.00%; P <.05) but was ineffective on healthy B-lymphocytes (50.88%; max. value, 58.18%; min. value, 41.10%; P <.05) compared with untreated control groups. No living cells remained following treatment with the combination of anti-miR-146a + anti-miR-155 + anti-miR-181a + anti-let-7e and prednisolone (viability percentage mean, 0.00%; P <.0001).
The combination of all anti-miRs and IC50 dose of prednisolone induced an average of 87.3-fold more apoptosis in leukemia cells than in control cells (P <.0001), while no significant apoptosis occurred in the healthy B-lymphocytes (mean fold change, 0.61; P >.05). Anti-miR application also appeared have effects on cell cycle and proliferation in leukemia cells, and the effects were increased when prednisolone was also administered. However, these effects appeared to be minimal in healthy cells.
“The silencing of the critical leukemia regulatory miRNAs, namely, miR-146a, miR-155, and miR-181a may be regarded as an antileukemic strategy to enhance the effect of prednisolone treatment,” the authors concluded. “Further studies involving different ALL cell lines and diverse miRNAs should be performed to reveal the potential effects and possible use of anti-miR agents in ALL therapy in the future.”
Durmaz B, Bagca BG, Cogulu O, et al. Antileukemic effects of anti-miR-146a, anti-miR-155, anti-miR-181a, and prednisolone on childhood acute lymphoblastic leukemia. Biomed Res Int. 2021;2021:3207328. Published 2021 Nov 28. doi:10.1155/2021/3207328