The role of exosomes and miRNAs in drug‐resistance of cancer cells

Abstract

Chemotherapy, one of the principal approaches for cancer patients, plays a crucial role in controlling tumor progression. Clinically, tumors reveal a satisfactory response following the first exposure to the chemotherapeutic drugs in treatment. However, most tumors sooner or later become resistant to even chemically unrelated anticancer agents after repeated treatment. The reduced drug accumulation in tumor cells is considered one of the significant mechanisms by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell membrane. The mechanisms of treatment failure of chemotherapeutic drugs have been investigated, including drug efflux, which is mediated by extracellular vesicles (EVs). Exosomes, a subset of EVs with a size range of 40-150 nm and a lipid bilayer membrane, can be released by all cell types. They mediate specific cell-to-cell interactions and activate signaling pathways in cells they either fuse with or interact with, including cancer cells. Exosomal RNAs are heterogeneous in size but enriched in small RNAs, such as miRNAs. In the primary tumor microenvironment, cancer-secreted exosomes and miRNAs can be internalized by other cell types. MiRNAs loaded in these exosomes might be transferred to recipient niche cells to exert genome-wide regulation of gene expression. How exosomal miRNAs contribute to the development of drug resistance in the context of the tumor microenvironment has not been fully described. In this review, we will highlight recent studies regarding EV-mediated microRNA delivery in formatting drug resistance. We also suggest the use of EVs as an advancing method in antiresistance treatment.

BMP4 Upregulation Is Associated with Acquired Drug Resistance and Fatty Acid Metabolism in EGFR-Mutant Non-Small-Cell Lung Cancer Cells

“…In our previous review, we reported a significant relationship between exosomes and miRNAs in the drug resistance of cancer cells 11 . In the present study, we observed that the expression of exosomal miR-139-5p is also downregulated in PC9-Gef cells compared to PC9 cells (Figure 1C).…”

“…Recent studies revealed that miRNAs might be applicable as potential biomarkers to predict responses to chemotherapy and survival of patients with malignant tumors 11 . Indeed, downregulation of miR-139-5p was observed in colorectal cancer, 23 hepatocellular carcinoma (HCC), 42 and NSCLC 26 .…”

“…Accumulating evidence also suggests that microRNAs (miRNAs) play a significant role in epigenetically modulating various phenotypic changes in cancer cells 11, 12, 13, 14, 15. Indeed, miRNAs may affect genetic programs through post-transcriptional silencing of target genes, either by inhibiting the translation of target mRNAs or by promoting their degradation 16, 17.…”

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

“…However, modern chemotherapy using various antitumor drugs either incompletely kills the malignant cells or causes fatal dysfunction and serious systemic toxicity (8). In addition, tumor drug resistance is a major problem associated with chemotherapy and involves numerous factors, including anticancer drug potency, tumor cell-drug reaction, the tumor microenvironment and tumor cell heterogeneity (9). Numerous apoptosis-inducing agents are also substrates and inducers of drug transporters, including P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) (10,11).…”

Exosomes as a novel pathway for regulating development and diseases of the skin (Review)

“…They are important mediators of cell-to-cell communication, which is involved in multiple processes, including the immune response, apoptosis, angiogenesis and inflammation (11). Cells secrete exosomes that present signal molecules to nearby or distant tissues or cells, serving a regulatory role (12).…”