P-glycoprotein (P-gp)-driven cancer drug resistance: biological profile, non-coding RNAs, drugs and nanomodulators

• Cancer therapy has been compromised by the development of drug resistance. • The upregulation of P-glycoprotein (P-gp) can induce chemoresistance. • The overexpression of oncogenic factors mediates P-gp. • Non-coding RNAs can regulate P-gp in cancers. • Nanoparticles can affect P-gp and bypass P-gp for overcoming drug resistance. Drug resistance has compromised the efficacy of chemotherapy. The dysregulation of drug transporters including P-glycoprotein (P-gp) can mediate drug resistance through drug efflux. In this review, we highlight the role of P-gp in cancer drug resistance and the related molecular pathways, including phosphoinositide 3-kinase (PI3K)–Akt, phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), along with non-coding RNAs (ncRNAs). Extracellular vesicles secreted by the cells can transport ncRNAs and other proteins to change P-gp activity in cancer drug resistance. P-gp requires ATP to function, and the induction of mitochondrial dysfunction or inhibition of glutamine metabolism can impair P-gp function, thus increasing chemosensitivity. Phytochemicals, small molecules and nanoparticles have been introduced as P-gp inhibitors to increase drug sensitivity in human cancers.