Perspectives of P-glycoprotein modulating agents in oncology and neurodegenerative diseases: pharmaceutical, biological, and diagnostic potentials.

Human ATP binding cassette (ABC) transporters belong to a family of 49 genes classified into seven subfamilies: ABCA, ABC-B, ABC-C, ABC-D, ABC-E, ABC-F, ABC-G. Some of these transporters are involved in multidrug resistance (MDR), in particular ABC-B1, better known as Pglycoprotein (P-gp), ABC-G2, better known as breast cancer resistance protein (BCRP), and ABC-C1-6, also known as multidrug resistance associated proteins (MRP1-6). 3 These transporters are overexpressed in several tumor cell lines and are responsible for drug efflux out of the cells. They use the energyofATPhydrolysis to extrude compoundsbya complex translocation process. Three models for P-gp translocation have been suggested: (1) pore, (2) flippase, and (3) hydrophobic vacuum cleaner models. In the pore model, drugs binding P-gp to the cytosol are transported out through a protein channel. In the flippase model, P-gp flips drugs that are transported from the inner to the outer compartment of the plasmamembrane against a concentration gradient. In the hydrophobic vacuum cleaner model, molecules recognized by P-gp in the lipid bilayer enter the protein from the membranous site and exit through the central cavity. P-gp contains 12 transmembrane helices organized in two membrane spanning domains (MSDs), each containing six transmembrane helices, and two nucleotide binding domains (NBDs) responsible for ATP binding. BCRP is a “half transporter” because it is formed by only one MSD and one NBD although it dimerizes to be fully active. MRPs differ from P-gp because they display three MSDs, and the additional domain contains five transmembrane domains. This review will focus on the physiological and pathological role of P-gp and will highlight the involvement of this protein both in MDR of tumors and in the physiological function of several barriers. P-gp overexpression is a significant factor in chemotherapy failure due to the ability of this pump to limit the cell accumulation of antineoplastic drugs. Moreover, P-gp is expressed in barriers such as the blood-brain barrier (BBB), bloodcerebro spinal fluid (B-CSF) barrier, and blood-testis barrier (BTB). It modulates the absorption and excretion of xenobiotics across these barriers. P-gp is localized at the apical membranes of liver, kidney, placenta, and the villus tip of enterocytes in the gut. In the gut, P-gp displays a strategic activity modulating access of drugs to the CYP3A4 enzyme, thereby regulating drug metabolism and absorption. 1.1. P-gp Involvement in Cancer and CNS Diseases.MDR is a complex phenomenon that is caused by tumor microenvironment changes or cancer cell-specific factors. Cancer cell-specific factors can occur at different levels: (i) increased drug efflux or decreased drug influx; (ii) drug inactivation; (iii) drug target modification; (iv) apoptosis evasion. The first of these mechanisms can be mediated by plasma membrane transporters such as P-gp. Asmentioned above, high levels of P-gp are reported in the luminal membrane of the endothelial cells constituting the BBB, B-CSF, and BTB. This strategic localization gives P-gp a crucial physiologically role in keeping drugs in the blood. P-gp exerts a protective function in the BBB; indeed, recent studies have reported a potential correlation between P-gp activity and/or expression in CNS disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and epilepsy. AD, a neurodegenerative disorder characterized by a progressive loss of cognitive function, evolves as several forms of dementia that display insoluble β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs). Aβ secretion is *To whom correspondence should be addressed. Phone: þ39-0805442727. Fax þ39-080-5442231. E-mail: colabufo@farmchim.uniba.it. Abbreviations: Aβ, β-amyloid; AB, apical-basolateral; ABC, ATP binding cassette; AD, Alzheimer’s disease; AML, acute myelogenous leukemia; ATP, adenosine 50-triphosphate; BA, basolateral-apical; Bmax, maximal bound; BBB, blood-brain barrier; BCRP, breast cancer resistance protein; B-CSF, blood-cerebro spinal fluid; BTB, blood-testis barrier; Caco-2, human colonic carcinoma; calcein-AM, calcein acethoxymethyl ester; CD56þ, peripheral blood mononuclear cells; CHOP, cyclophosphamide, hydroxydaunorubicin (adriamycin), oncovin (vincristine), prednisone/prednisolone; CNS, central nervous system; C-PIB, C-Pittsburgh compound B; CYP3A4, cytochrome P-4503A4; DV, distribution volume; FDA, Food and Drug Administration; F-FDDNP, F(2-(1-{6-[(2-[F]fluoroethyl(methyl)amino]-2-naphthyl}ethylidene)malononitrile; FMZ, flumazenil; GI, gastrointestinal; HCT-8, human colorectale adenocarcinoma; ISF, interstitial fluid; Kd, dissociation constant; LBs, Lewy bodies; LLC-PK1, porcine kidney cell line; LRP1, low density lipoprotein receptor-related protein; MDCK, Madin-Darby canine kidney; MDE, multidrug efflux; MDR, multidrug resistance;MPPþ, 1-methyl-4-phenylpyridinium;MRP,multidrug resistance associated proteins;MSA, multisystem atrophy;MSD, membrane spanning domain; MTD, maximum tolerated dose; MTL, medial temporal lobe; NBD, nucleotide binding domain; NFTs, neurofibrillary tangles; NSCLC, non-small-cell lung cancer; PAHG, hippocampus, parahippocampal, ambient gyrus; Papp, apparent permeability; PD, Parkinson’s disease; PET, positron emission tomography; P-gp, Pglycoprotein; PSP, progressive supranuclear palsy; SCLC, small-cell lung cancer; SNP, single nucleotide polymorphism; SPECT, single photon emission computed tomography; T8, T-suppressor cells; TLE, temporal lobe epilepsy.