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.
Highlights
Evaluation of drug-drug synergistic interactions are important in medicine (Zhao, Au & Wientjes, 2010)
We recently reported that doxorubicin, a well-known DNA-damaging agent (DDA) (Gavet & Pines, 2010) and methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC), a recently introduced Microtubule Targeting Agent (MTA) (Hasanpourghadi, Pandurangan & Mustafa, 2017) in combination caused a further reduction of 39.5% and 56.8% of tumor volume compared to doxorubicin or MBIC monotherapy respectively (Hasanpourghadi et al, 2017)
MBIC displayed a synergistic effect with doxorubicin in MCF-7 and MDA-MB-231 cell lines
Summary
Evaluation of drug-drug synergistic interactions are important in medicine (Zhao, Au & Wientjes, 2010). The expression profiling of selective miRNAs is associated with the sensitivity of the cancer cells to the anticancer drugs. Expanding the knowledge about those miRNAs involved in the expression of proteins that are targets of respective drugs is becoming increasingly important (Zheng et al, 2010). The importance of the bi-functional role of survivin protein was reported, in order to increase the benefits that a patient with breast cancer may receive from anticancer effect of MBIC (Hasanpourghadi et al, 2017). In the present study we examined the association of several miRNAs that are reported to be involved in the expression of survivin protein following treatment with anticancer drugs. In the present study we examined the association of several miRNAs that are reported to be involved in the expression of survivin protein following treatment with anticancer drugs. miR-34a, miR-320a and miR-542 are reported to target mRNA transcripts of the anti-apoptotic protein survivin (Cao et al, 2013; Diakos et al, 2010; Yoon et al, 2010)
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