ABSTRACT
Introduction
Multi-drug resistance (MDR) is a hindrance toward the successful treatment of cancers. The primary mechanism that gives rise to acquired chemoresistance is the overexpression of adenosine triphosphate-binding cassette (ABC) transporters. The dysregulation of non-coding RNAs (ncRNAs) is a widely concerned reason contributing to this phenotype.
Areas covered
In this review, we describe the role of intracellular and exosomal ncRNAs including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in ABC transporters-induced tumor MDR. Meanwhile, we will introduce the potential therapeutic strategies which reverse MDR in terms of reducing the expression of ABC transporters via targeting ncRNAs, like nucleic acid delivery with nanoparticles as well as miRNAs-targeted small molecular compounds.
Expert opinion
The dysregulated ncRNAs-mediated overexpression of ABC transporters in chemo-resistant cancer is not negligible. Finding out the underlying mechanism may provide a theoretical basis for clinical therapy of cancer MDR, and the emergence of new approaches for gene therapy targeting ncRNAs to suppress ABC transporters makes reversing cancer MDR possible despite its clinical application requires further investigations. Also, the discovered ncRNAs regulating ABC transporters in chemo-resistant cancers are just a tip of the iceberg of the genetic transcripts, especially for circRNAs, which justify more concern.
Abbreviations: MDR, multi-drug resistance; ABC, adenosine triphosphate-binding cassette; NcRNAs, non-coding RNAs; MiRNAs, microRNAs; LncRNAs, long non-coding RNAs; CircRNAs, circular RNAs; CeRNAs, competing endogenous RNAs; 3′UTR, 3′-untranslated regions; SLC, solute carrier; ABCB1/MDR1, ABC subfamily B member 1; ABCG2/BCRP, ABC subfamily G member 2; ABCCs/MRPs, ABC subfamily C 1 to 12; DLL1: Delta-like protein 1; DTX, docetaxel; DOX/ADM/ADR, doxorubicin/adriamycin; PTX, paclitaxel; VBL, vinblastine; VCR, vincristine; MTX, methotrexate; CDDP/DDP, cisplatin/cis-diaminedichloroplatinum; OXA/L-OHP, oxaliplatin; TMZ, temozolomide; 5-FU, 5-fluorouracil; MTA, pemetrexed; NSCLC, non-small cell lung carcinoma; HCC, hepatocellular carcinoma; CRC, colorectal carcinoma; RB, retinoblastoma; RCC, renal cell carcinoma; OS, osteosarcoma; PDAC, pancreatic ductal adenocarcinoma; TNBC, triple-negative breast cancer.
Article highlights
ABC transmembrane transporters are involved in the efflux of several anti-tumor drugs, and most ABC transporters like ABCB1, ABCCs and ABCG2 are overexpressed in chemo-resistant cancers, which may contribute to chemotherapy failure.
Intracellular or exosomal non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) as well as circRNAs are dysregulated in chemo-resistant cancer patients and associated with the progression of cancer MDR.
The abnormal expression of ABC transporters is regulated by intracellular or exosomal ncRNAs through diverse mechanisms.
ncRNAs are identified as potential therapeutic targets for chemo-resistant cancers, and exosomal ncRNAs act as potential diagnostic biomarkers for cancer MDR.
Several strategies intervene ncRNAs-ABC transporters axis for cancer MDR therapy, such as delivering ncRNA mimics or antisense oligonucleotide of ncRNAs and small molecular compounds.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Additional information
Funding
Notes on contributors
Haihong Hu
Su Zeng, Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310,006, China, e-mail: [email protected]