Combinatory Treatment with miR-7-5p and Drug-Loaded Cubosomes Effectively Impairs Cancer Cells

Abstract

Background: Multidrug resistance (MDR) is an emerging problem in the treatment of cancer. Therefore, there is a necessity for novel strategies that would sensitize tumor cells to the administered chemotherapeutics. One of the innovative approaches in fighting drug-resistant tumors is the treatment of cancer with microRNA (miRNA), or the use of cubosomes (lipid nanoparticles) loaded with drugs. Here, we present a study on a novel approach, which combines both tools. Methods: Cubosomes loaded with miR-7-5p and chemotherapeutics were developed. The effects of drug- and miRNA-loaded vehicles on glioma- (A172, T98G), papillary thyroid- (TPC-1) and cervical carcinoma-derived (HeLa) cells were analyzed using molecular biology techniques, including quantitative real-time PCR, MTS-based cell proliferation test, flow cytometry and spheroids formation assay. Results: The obtained data indicate that miR-7-5p increases the sensitivity of the tested cells to the drug, and that nanoparticles loaded with both miRNA and the drug produce a greater anti-tumor effect in comparison to the free drug treatment. It was found that an increased level of apoptosis in the drug/miRNA co-treated cells is accompanied by an alternation in the expression of the genes encoding for key MDR proteins of the ABC family. Conclusions: Overall, co-administration of miR-7-5p with a chemotherapeutic can be considered a promising strategy, leading to reduced MDR and the induction of apoptosis in cancer cells.

The Role of miRNA-7 in the Biology of Cancer and Modulation of Drug Resistance

“…MiR-7 regulates genes involved in repairing neurons [ 89 ] and enables synaptic plasticity [ 90 ]. Considering the importance of miR-7 in brain tissue, it is not surprising that its downregulation results in the occurrence of pathological conditions like Parkinson’s disease [ 91 ] and brain tumors [ 92 , 93 , 94 , 95 ]. On the other hand, upregulation of miR-7 is correlated with progression of Alzheimer’s disease [ 96 ], schizophrenia [ 97 ], and neuroinflammatory processes [ 98 , 99 ].…”

“…As already mentioned, miR-7 plays a crucial role in the development of the CNS and additionally, its important role in GB progress was also highlighted. Various groups reported significantly decreased levels of miR-7 in GB tissues [ 92 , 153 ]. Jia et al (2019) linked miR-7 and GB resistance to TMZ.…”

“…Our own studies also highlighted the role of miR-7 in the development of drug resistance in GB [ 92 ]. The experiments were performed using GB-derived drug-sensitive cells (A172), as well as the T98G drug-resistant cell line.…”

“…Moreover, it was shown that treatment of drug-resistant T98G cells with miR-7 mimic results in downregulation of key multidrug efflux pumps. It was concluded that the effectiveness of combinatory treatment with miR-7 and chemotherapeutics likely results from miR-7-mediated suppression of MDR-encoding genes [ 92 ].…”

“…MiRNA-7 is downregulated in most cancer types and its depletion affects the expression of various proteins involved in apoptosis, EGFR signaling pathways, and MDR. In most cases, miRNA-7 has been shown to increase the sensitivity of tumor cells to the therapeutic agents [ 92 , 135 , 146 ]. Therefore, miR-7 can be considered as a very promising putative target in cancer therapy.…”