Associate editor: D. SpinaHow can we best use structural information on P-glycoprotein to design inhibitors?
Section snippets
P-glycoprotein: a brief history of resistance
A significant proportion of annual cancer deaths have been attributed to the failure of chemotherapy to produce cytotoxicity in tumors (Goldman, 2003). This inability is due to resistance, which may be an inherent property of the specific cancer type or is acquired following initial chemotherapy. Resistance to chemotherapy has been investigated using animal models and cultured cells since the late 1950s although the underlying mechanism(s) did not appear till the 1970s. For example, independent
P-glycoprotein expression: its importance in cancer resistance
Following the primary identification of P-gp as a mediator of drug resistance, its expression in clinical samples was examined to assess its fidelity as an indicator for patient prognosis. Two of the first studies (Cordon-Cardo et al., 1989, van der Valk et al., 1990) demonstrated that P-gp expression was highest in tumors from colon, adrenal, pancreatic, mammary, and renal tissue, even in the absence of any prior chemotherapy. These studies also demonstrated that P-gp was expressed in many
The earliest stage of P-glycoprotein inhibitor development
The first attempt at pharmacological modulation of P-gp was in 1981 following the observations by Tsuruo et al. (1981) that verapamil could sensitize vincristine resistant P388 leukemia cells to vincristine and vinblastine. By current standards, verapamil seems a curious choice to modulate P-gp mediated transport. The initial justifications for verapamil included its ability for nonspecific modulation of secretory pathways, to alter protein mediated Ca2+ transport and a propensity to
P-gp inhibition: a more rational approach
Based on these trials it was clear that a more sophisticated approach was required to achieve clinical inhibition of P-gp. The obvious approach was to use the available in vitro assays to ascertain any common pharmacophoric elements on substrates for P-gp. The first attempt was undertaken by Zamora et al. (1988) and much of their simple framework is still utilized in drug development. More specifically, P-gp substrates display lipid solubility at a physiological pH, planar appearance, and
P-gp inhibition: pharmacology and chemistry unite
The power of combinatorial chemistry has been utilized in the 3rd generation of P-gp inhibitors in order to develop novel compounds without the limitations of the first 2 generations. Four promising lead compounds have thus far been developed (Table 1) from high throughput methods (Hyafil et al., 1993, Slate et al., 1995, Roe et al., 1999, Newman et al., 2000, Benet and Cummins, 2001). The most promising feature of these compounds is their ability to modulate P-gp function at the nanomolar
P-gp inhibition: where are we after 30 years and where to now?
The combinatorial and systematic modification chemical approaches have thus far only produced a handful of novel selective and potent P-gp inhibitors. Unfortunately, some of these inhibitors are associated with unwanted pharmacokinetic drug interactions that may limit their clinical applicability. What is being done and what strategies should we employ in order to achieve the aim of chemosensitization through inhibition of P-gp? A popular approach in recent years has been the use of fruit or
Structural approaches to inhibitor design
Structure-based design is an iterative process whereby the protein is analyzed and a putative ligand is designed and synthesized and its biological activity assessed (Fig. 2). Historically the favored approaches of lead compound generation and identification were combinatorial chemistry and diversity-based high-throughput screening of compound libraries. Over the last decade the rates at which high-resolution 3-dimensional (3D) structures of protein targets have become available has rapidly
P-glycoprotein as a model for inhibitor design
The relevance of P-gp to cancer chemoresistance and drug pharmacokinetics has been documented in 1 P-glycoprotein: a brief history of resistance, 2 P-glycoprotein expression: its importance in cancer resistance, 3 The earliest stage of P-glycoprotein inhibitor development. It is apparent from this discussion that P-gp represents an important molecule for design of modulatory compounds. As with all ABC transporters, the minimal functional unit consists of 4 core domains (2 transmembrane domains
Candidate sites for putative P-glycoprotein inhibitors
Biochemical studies have identified critical areas as potential sites of action for P-gp inhibitors: (i) drug binding/efflux, (ii) the NBD, and (iii) the residues involved in communication pathways. The model in Fig. 3b–d highlights residues or regions of the protein thought to be involved in these functions. The drug-binding sites are the classic targets of inhibitor design as highly efficacious modulators (nontransportable drug analogues) are an efficient way at blocking substrate drugs from
References (138)
- et al.
The power of the pump: mechanisms of action of P-glycoprotein (ABCB1)
Eur J Pharm Sci
(2006) - et al.
The drug efflux-metabolism alliance: biochemical aspects
Adv Drug Deliv Rev
(2001) - et al.
Molecular modeling as a powerful technique for understanding small-large molecules interactions
Farmaco
(2002) - et al.
Characterization of the azidopine and vinblastine binding site of P-glycoprotein
J Biol Chem
(1992) - et al.
Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump
Blood
(2004) - et al.
The translocation mechanism of P-glycoprotein
FEBS Lett
(2006) Structure of MsbA from Vibrio cholera: A multidrug resistance ABC transporter homolog in a closed conformation
J Mol Biol
(2003)- et al.
Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein
J Biol Chem
(1987) Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells
Biochim Biophys Acta
(1973)- et al.
Localization of the iodomycin binding site in hamster P-glycoprotein
J Biol Chem
(1997)
Allosteric modulation of the human P-glycoprotein involves conformational changes mimicking catalytic transition intermediates
Arch Biochem Biophys
Reduced cyclosporin accumulation in multidrug-resistant cells
Biochem Biophys Res Commun
Transport energetics of the folic acid analogue, methotrexate, in L1210 leukemia cells. Enhanced accumulation by metabolic inhibitors
J Biol Chem
P-glycoprotein and multidrug resistance
Curr Opin Genet Dev
Major photoaffinity drug labeling sites for iodoaryl azidoprazosin in P-glycoprotein are within, or immediately C-terminal to, transmembrane domains 6 and 12
J Biol Chem
A phase I/II study of the MDR modulator Valspodar (PSC 833) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia
Leuk Res
Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily
Cell
Reversal of multidrug resistance by calcium channel blocker SR33557 without photoaffinity labelling of P-glycoprotein
J Biol Chem
A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants
Biochim Biophys Acta
Drug-grapefruit juice interactions
Mayo Clin Proc
Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter
Structure
Predicting multidrug resistance-related protein and P-glycoprotein expression with technetium-99m tetrofosmin mammoscintigraphy
Breast
Identification of residues in the drug-binding site of human P-glycoprotein using a thiol-reactive substrate
J Biol Chem
Defining the drug-binding site in the human multidrug resistance P-glycoprotein using a methanethiosulfonate analog of verapamil, MTS-verapamil
J Biol Chem
Location of the rhodamine-binding site in the human multidrug resistance P-glycoprotein
J Biol Chem
Substrate-induced conformational changes in the transmembrane segments of human P-glycoprotein. Direct evidence for the substrate-induced fit mechanism for drug binding
J Biol Chem
Crystal structure of the SMC head domain: An ABC ATPase with 900 residues antiparallel coiled-coil inserted
J Mol Biol
Allosteric modulation of human P-glycoprotein. Inhibition of transport by preventing substrate translocation and dissociation
J Biol Chem
Allosteric modulation bypasses requirement for ATP hydrolysis in regnerating low-affinity transition state conformation of human P-glycoprotein
J Biol Chem
Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives
Bioorg Med Chem Lett
Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis
J Biol Chem
Three-dimensional structures of the mammalian multidrug resistance P-glycoprotein demonstrate major conformational changes in the transmembrane domains upon nucleotide binding
J Biol Chem
Three-dimensional structure of P-glycoprotein: The transmembrane regions adopt an asymmetric configuration in the nucleotide-bound state
J Biol Chem
The topography of transmembrane segment six is altered during the catalytic cycle of P-glycoprotein
J Biol Chem
The coupling mechanism of P-glycoprotein involves residue L339 in the sixth membrane spanning segment
FEBS Lett
Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance
Toxicol Lett
Biochemical, cellular, and pharmacological aspects of the multidrug transporter
Annu Rev Pharmacol Toxicol
Phase I/II trial of the multidrug-resistance modulator valspodar combined with cisplatin and doxorubicin in refractory ovarian cancer
J Clin Oncol
Phase I trial of doxorubicin with cyclosporine as a modulator of multidrug resistance
J Clin Oncol
A phase I/II study of infusional vinblastine with the P-glycoprotein antagonist valspodar (PSC 833) in renal cell carcinoma
Clin Cancer Res
Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: Consensus recommendations
Cancer Res
Phase I study of vinblastine and verapamil given by concurrent iv infusion
Cancer Treat Rep
Phase I trial of high-dose tamoxifen as a modulator of drug resistance in combination with daunorubicin in patients with relapsed or refractory acute leukemia
Leukemia
A structure-function relationship among reserpine and yohimbine analogues in their ability to increase expression of mdr1 and P-glycoprotein in a human colon carcinoma cell line
Mol Pharmacol
Imaging multidrug resistance P-glycoprotein transport function using microPET with technetium-94m-sestamibi
Mol Imaging
Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer
J Clin Oncol
Mammalian ABC transporters in health and disease
Annu Rev Biochem
Clinical trial of continuous infusion verapamil, bolus vinblastine, and continuous infusion VP-16 in drug-resistant pediatric tumors
Cancer Res
P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma
N Engl J Med
P-glycoprotein expression: Critical determinant in the response to osteosarcoma chemotherapy
J Natl Cancer Inst
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2023, European Journal of Medicinal ChemistryZebrafish (Danio rerio) ability to activate ABCC transporters after exposure to glyphosate and its formulation Roundup Transorb®
2020, ChemosphereCitation Excerpt :The most studied ABC transporters for xenobiotic extrusion are glycoprotein P (PgP/ABCB4 for D. rerio), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance proteins (MRPs/ABCC). Pgp is located in the apical region of polarized cells and it transports moderately hydrophobic, small, positively charged (cation) or neutral substances (Litman et al., 2001; Higgins, 2007; McDevitt and Callaghan, 2007), participating in the elimination of phase I metabolites from the biotransformation process (compounds that have undergone oxidation, reduction and/or hydrolysis reactions) (Goksøyr and Förlin, 1992; Ambudkar et al., 1999). The ABCG2 protein is also located in the apical region of polarized cells and plays an important role in clinical resistance to cancer drugs.
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