Despite significant advances in the development of new anticancer drugs, the emergence of multidrug resistance (MDR) remains a major unresolved obstacle for efficacious cancer chemotherapy (Nussinov et al., 2021, Lei et al., 2020). MDR can be defined as a decrease or loss of efficacy to a variety of different drugs that are structurally and functionally distinct from the original drug (Robey et al., 2018). MDR in cancer cells can occur by 1) overexpression of certain ABC transporters that extrude various anticancer drugs from cancer cells (Fletcher et al., 2016, Pote and Gacche, 2023); 2) a decrease in drug uptake (Muley et al., 2020); 3) an increase in the DNA damage response and repair (Tiek and Cheng, 2022, Li et al., 2021); 4) an avoidance or evasion of cell death (Neophytou et al., 2021, Vaidya et al., 2022); 5) an increase in the biotransformation of anticancer drugs to less efficacious or inactive metabolites (Lopes-Rodrigues et al., 2017); 6) sequestration of drugs within organelles (Halaby, 2019, Zhitomirsky and Assaraf, 2016); 7) mutations in cellular molecular targets that decrease or prevent the interaction of drugs with their cellular target (Zhang et al., 2023) and 8) an increase in the tolerance of cancer cells to stressful or non-homeostatic conditions in the tumor microenvironment (De Las Rivas et al., 2021, Fan et al., 2023). Numerous studies over the past 5 decades indicate that the overexpression of certain ABC transporters in specific types of cancer cells represents the major mechanism that produces MDR (da Silveira et al., 2020; Kadioglu et al., 2020; Mandic et al., 2023; Nimisha et al., 2023; Paprocka et al., 2017; Xiao et al., 2021).

Non-coding RNAs (ncRNAs) refer to RNA transcripts that do not have protein-coding function but they play important roles in diverse biological processes, such as transcription, post-transcriptional processing and translation (Gao et al., 2020, Hombach and Kretz, 2016, Kopp and Mendell, 2018, Statello et al., 2021, Yang et al., 2016). Numerous ncRNAs display tissue-specific expression patterns (de Goede et al., 2021) and some are involved in regulating cancer progression and chemoresistance (Toden et al., 2021, Wang et al., 2019, Yan and Bu, 2021). According to different classification criteria (St Laurent et al., 2015), ncRNAs can be divided into a variety of categories (Table 1). Based on their cellular functions, ncRNAs are classified into housekeeping ncRNAs (i.e., rRNAs and tRNAs) and regulatory ncRNAs (i.e., microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs)) (Hombach and Kretz, 2016). Based on their transcript length, ncRNAs can be divided into lncRNA (> 200 nucleotides) and short ncRNA (< 200 nucleotides), including miRNAs, small interfering RNAs (siRNAs) and piwi-interacting RNAs (piRNAs) (Taft et al., 2010). Furthermore, ncRNAs can also be categorized based on their genomic origins (including sense or antisense ncRNAs, bidirectional ncRNAs, intronic ncRNAs and intergenic ncRNAs) or their subcellular localization (e.g., small nuclear RNAs and cytoplasm-located siRNAs) (Asim et al., 2021; Dozmorov et al., 2013; Takemata and Ohta, 2017). An increasing number of publications suggest that the aberrant regulation of ncRNAs is driving the overexpression of ABC transporters in MDR cancer cells (Zhang et al., 2020, Wang et al., 2021).

This review provides an update about the various ncRNAs that have been reported to regulate ABC transporters and mediate MDR in cancer cells. Emerging strategies that target these ncRNAs regulatory pathway, with an aim to overcome MDR, will also be discussed.