ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal

Abstract

One of the major problems related with anticancer chemotherapy is resistance against anticancer drugs. The ATP-binding cassette (ABC) transporters are a family of transporter proteins that are responsible for drug resistance and a low bioavailability of drugs by pumping a variety of drugs out cells at the expense of ATP hydrolysis. One strategy for reversal of the resistance of tumor cells expressing ABC transporters is combined use of anticancer drugs with chemosensitizers. In this review, the physiological functions and structures of ABC transporters, and the development of chemosensitizers are described focusing on well-known proteins including P-glycoprotein, multidrug resistance associated protein, and breast cancer resistance protein.

Figure 1

Schematic structural organization of P-glycoprotein. Each half contains a highly hydrophobic domain with 6 transmembrane α-helices involved in chemotherapeutic drug efflux, and a hydrophilic domain located at the cytoplasmic face of the membrane, nucleotide binding domain 1(NBD1) or NMD 2, containing an ATP-binding site with cheracteristic Walker motifs A and B and the S signature of ABC transporters. The two half molecules are separated by a highly charged "linker region which is phosphorylated at several sites by protein kinase C and the first extracellular loop is heavily N-glycosylated [3].

Figure 2

Comparison of nucleotide free-Pgp (nf-Pgp) and Pgp-AMP-PNP (Pgp-AMP-PNP) three-dimensional structures. A, stereo pair of the nf-Pgp three-dimensional structure, displayed using netting at 1.0 σ (red) and 1.5 σ (yellow) above the mean density level and viewed perpendicular to the crystal plane from the more heavily stained side (corresponding to the extracellular surface). B, equivalent views of the Pgp-AMP-PNP structure. The arrow indicates the gap along one side of the central pore. The locations of the three discrete densities A, B, and C are indicated. C, stereo pair of a side view of Pgp-AMP-PNP with the same color scheme as above. The directions of the principle crystallographic axes a and b are shown. Scale bar = 2.2 nm. AMP-PNP, non-hydralizable ATP analogue [176].

Figure 3

Model of the NBD conformational change by the drug binding to TDM. [178].

Figure 4

Proposed schematic model of NBDs showing the relative positions of different nucleotide- and effector-binding sites. MANT-ATP binding is prevented by preincubation with antiprogestin RU-486 and bound MANT-ATP is displaced by Ru-486, suggesting the existence of a cytosolic steroidal-interacting region adjacent to the ATP-binding site. Since the flavonoid binding is prevented by preincubation with ATP and RU-486, bound flavonoids most likely cover both ATP site and the vicinal steroid site. MANT, 2'(3')-N-methylanthraniloyl [3].