• The role of exosomal circular RNAs and their underlying mechanisms in cancer drug resistance
  • Nooshafarin Shirani,1,* Neda Abdi,2
    1. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
    2. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.


  • Introduction: Drug resistance has long been a topic in many cancer studies. Despite the efforts and successes in cancer treatment, anticancer drug resistance remains a major problem in the treatment of this disease and has a significant impact on clinical outcomes. Recent studies have highlighted the role of exosomal circular RNAs (circRNAs) as crucial mediators in exerting drug resistance in various cancers. Exosomes are a specialized group of small secretory vesicles found in various body fluids that facilitate cell-cell communication and the exchange of various biological information through the transfer of biomolecules, including circRNAs. circRNAs are a new type of ncRNA with a closed RNA structure that has been shown to play an essential role in controlling various genes and signaling pathways. This review addresses the emerging evidence linking exosomal circRNA to the modulation of drug resistance mechanisms.
  • Methods: A comprehensive literature search was conducted, focusing on recent studies. Databases such as PubMed, Scopus, Google Scholar, and Web of Science were searched using keywords like "exosomes"," "circRNAs"," "exosomal circRNAs", "tumor microenvironment"," "drug resistance"," "chemotherapy resistance" and "cancer"." The selected studies were thoroughly analyzed to collect information on exosomal circRNAs, their mechanisms of action, the different types of circRNAs involved and their influence on drug resistance. Both in vitro and in vivo research was included to provide a comprehensive overview of the current research landscape.
  • Results: The analysis revealed that exosomal circRNAs contribute to drug resistance via multiple mechanisms, including modulation of drug efflux pumps, alteration of apoptosis pathways, regulating cell cycle and controlling autophagy. For example, overexpression of circRNA CEP128 in temozolomide-resistant glioma cells leads to increased drug efflux and reduced intracellular drug accumulation through the upregulation of ATP-binding cassette G superfamily member 2 (ABCG2). According to another study, exosomes from oxaliplatin-resistant CRC cells released ciRS-122, which helps to increase glycolysis to generate more ATP for ABC drug efflux and pump oxaliplatin out of the cells. Furthermore, exosomal circ-PVT1 promoted DDP resistance in gastric cancer cells by modulating autophagy, invasion and apoptosis via the miR-30a-5p/YAP1 pathway. Additionally, their stability and prevalence in bodily fluids make them as ideal candidates for non-invasive liquid biopsies, revolutionizing cancer diagnostics and patient monitoring.
  • Conclusion: Exosomal circRNAs represent a novel and critical component in the landscape of anticancer drug resistance. Their capacity to regulate various cellular signaling pathways and affect gene expression highlights their promise as potential therapeutic targets. Targeting exosomal circRNAs as novel biomarkers or vehicles to deliver therapeutic circRNAs or RNAi molecules could enhance the efficacy of existing treatments and overcome drug resistance. A deeper understanding of the role of exosomal circRNAs in drug resistance not only sheds new light on cancer biology, but also paves the way for new therapeutic strategies. However, further research is needed to fully elucidate their mechanisms and develop strategies to inhibit their function in resistant cancer cells.
  • Keywords: exosomes, circRNAs, exosomal circRNAs, drug resistance, cancer