Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases

Abstract

The treatment of brain tumors and neurodegenerative diseases, represents an ongoing challenge. In Central Nervous System (CNS) the achievement of therapeutic concentration of chemical agents is complicated by the presence of distinct set of efflux proteins, such as ATP-Binding Cassette (ABC) transporters localized on the Blood-Brain Barrier (BBB). The activity of ABC transporters seems to be a common mechanism that underlies the poor response of CNS diseases to therapies.The molecular characterization of Breast Cancer Resistance Protein (BCRP/ABCG2), as an ABC transporter conferring multidrug resistance (MDR), has stimulated many studies to investigate its activity on the BBB, its involvement in physiology and CNS diseases and its role in limiting the delivery of drugs in CNS.In this review, we highlight the activity and localization of BCRP on the BBB and the action that this efflux pump has on many conventional drugs or latest generation molecules used for the treatment of CNS tumors and other neurodegenerative diseases.

Role of Human Breast Cancer Related Protein versus P-Glycoprotein as an Efflux Transporter for Benzylpenicillin: Potential Importance at the Blood-Brain Barrier

“…P-gp and BCRP are two major ABC efflux transporters abundantly expressed at the apical membrane of brain capillary endothelial cells. They act to limit the entry of a range of xenobiotic into brain[ 8 , 9 ]. Both of them have a wide variety of substrates including many therapeutic drugs, such as antibiotics and anticancer agents.…”

“…BCRP is widely distributed (brain, intestine, liver and kidney) and, like P-gp and MRPs, it transports a broad structurally and functionally diverse range of substrates including antibiotics, anticancer drugs and antivirals. There is a growing literature on the relative importance of BCRP at the human BBB[ 8 , 9 ]. Although BCRP substrate specificity differs from P-gp and MRPs, there is substantial overlap[ 9 – 13 ].…”

“…There is a growing literature on the relative importance of BCRP at the human BBB[ 8 , 9 ]. Although BCRP substrate specificity differs from P-gp and MRPs, there is substantial overlap[ 9 – 13 ]. While ABC transporters are neuroprotective when they deny entry of neurotoxic compounds into brain, they are also obstacles to CNS drug delivery.…”

Drug penetration in pediatric brain tumors: Challenges and opportunities

“…Transporters such as ATP‐binding cassette efflux transporters exclude many therapeutic agents and targeted therapies from entering the brain tissue 47 . Compounds that are high‐affinity substrates for efflux pumps, most commonly P‐glycoprotein (Pgp) and breast cancer‐resistance protein (BCRP), are known to have limited CNS distribution and are considered key parameters in pharmaceutical drug design 57,59–63 . As shown in Table 1, many chemotherapies currently used for treating pediatric brain tumors have high affinity for these transporters, implying reduced drug diffusion across the BBB.…”

Recent Developments in Nanomedicine for Pediatric Cancer

“…The blood-brain barrier (BBB) is a dynamic interface that separates the brain from the circulatory system to protect the brain from potentially harmful chemicals and pathogens and regulate the transport of essential nutrition to maintain a stable microenvironment [94]. The BBB is made up of continuous endothelial cells closely sealed by tight junctions and surrounded by astrocytes, pericytes, and the continuous basement membrane.…”