Revisiting strategies to target ABC transporter-mediated drug resistance in CNS cancer

A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier (BBB) and overexpression of ATP-binding cassette (ABC) transporters, which decrease drug penetration into the central nervous system and ultimately into tumors. It is noteworthy that the ABC transporters, ABCB1 [known as P-glycoprotein (P-gp)] and ABCG2 [known as breast cancer resistance protein (BCRP)], are overexpressed in brain tumors, including common gliomas. The co-presence of these transporters may negate the inhibition of either transporter, particularly if both transport the same anticancer drug. The cellular export of drugs by ABC transporters has been implicated in mediating resistance to anticancer drugs. However, the clinical relevance as a therapeutic target in human tumors remains a matter of contention. Although effective and clinically approved ABC transporter inhibitors could potentially overcome drug resistance, none are currently approved. Furthermore, the ABC transporter inhibitors in clinical trials produced low or no clinical efficacy, significant toxicities, and unsuitable pharmacokinetic profiles. Therefore, innovative approaches are needed to efficaciously and simultaneously inhibit these transporters to surmount anticancer drug resistance. This review emphasizes the clinical significance of ABC transporters in diminishing the efficacy of brain tumor treatments. The molecular alterations in BBB following brain tumor development, which are linked to various cancer therapies, are discussed. The overexpression of ABCB1 and ABCG2 at the BBB is discussed, potential strategies to decrease the export of chemotherapeutics by these transporters and the associated challenges and failures are discussed, and the implementation of novel approaches is considered.