The role of miRNAs 34a, 146a, 320a and 542 in the synergistic anticancer effects of methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) with doxorubicin in breast cancer cells

Abstract

Combination Index (CI) analysis suggested that MBIC and doxorubicin synergistically inhibited up to 97% of cell proliferation in ER+/PR+MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. Moreover, treatment of the breast cancer cells with the combined drugs resulted in lower IC50 values in contrast to the individual drug treatment. Small noncoding microRNAs (miRNA) may function as non-mutational gene regulators at post-transcriptional level of protein synthesis. In the present study, the effect of the combined treatment of MBIC and doxorubicin on the expression level of several miRNAs including miR-34a, miR-146a, miR-320a and miR-542 were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. These miRNAs have the potential to alter the protein level of survivin, the anti-apoptotic protein and reduce the metastatic activity in human breast cancer cell lines by interfering with the nuclear accumulation of NF-κB. Our results demonstrated the several fold changes in expression of miRNAs, which is drug and cell line dependent. This finding demonstrated a functional synergistic network between miR-34a, miR-320a and miR-542 that are negatively involved in post-transcriptional regulation of survivin in MCF-7 cells. While in MDA-MB-231 cells, changes in expression level of miR-146a was correlated with inhibition of the nuclear translocation of NF-κB. The overall result suggested that alteration in protein level and location of survivin and NF-κB by miR-34a, miR-320a, miR-146a and miR-542, remarkably influenced the synergistic enhancement of combined MBIC and doxorubicin in treatment of aggressive and less aggressive human breast cancer cell lines.

Porcine Milk Exosome MiRNAs Attenuate LPS-Induced Apoptosis through Inhibiting TLR4/NF-κB and p53 Pathways in Intestinal Epithelial Cells

“…It has been reported that, compared to individual miR-217 or miR-377 or transfections, the combination of miR-217 and miR-377 could not only reduce the expression of a HMOX1-3′UTR luciferase reporter but also reduce the protein expression and enzyme activity of heme oxygenase-1 (HMOX1, HO-1), indicating that the combination of miRNAs more effectively regulates HO-1 protein level in the presence of hemin than individual miRNAs . Furthermore, previous research demonstrated that miR-320a, miR-34a, and miR-542 have a synergistic function that is involved in the negative post-transcriptional regulation of survivin in MCF-7 cells . Previous studies have not reported the role of miR-4334, miR-219, and miR-338 in the NF-κB and p53 pathways.…”

“…46 Furthermore, previous research demonstrated that miR-320a, miR-34a, and miR-542 have a synergistic function that is involved in the negative post-transcriptional regulation of survivin in MCF-7 cells. 47 Previous studies have not reported the role of miR-4334, miR-219, and miR-338 in the NF-κB and p53 pathways. Furthermore, there is no report of the cooperative effects of these three miRNAs in TLRdependent inflammatory responses and in the apoptosis of intestinal epithelial cells.…”