ABC Efflux Pump-Based Resistance to Chemotherapy Drugs

Eckford, Paul D. W.; Sharom, Frances J.

doi:10.1021/cr9000226

Cited by 546 publications

(525 citation statements)

References 302 publications

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“…membrane protein structure | ABC transporter | nanobody-transporter complex T he mammalian adenosine triphosphate (ATP)-binding cassette (ABC) transporter P-glycoprotein (P-gp) is present in many tissues (1) and can detoxify cells by pumping xenobiotics across the membrane (2). A hallmark feature of this transporter is its ability to bind and transport an array of structurally diverse molecules ranging in size from 100 to 4,000 daltons (Da) (molecular mass) (3).…”

mentioning

confidence: 99%

“…Although its physiological function is not fully understood, the well-recognized role of P-gp in mediating multidrug resistance (MDR) in many types of cancers has made it a valid therapeutic target (5). P-gp also plays a significant role in the pharmacokinetics and bioavailability of drugs by mediating their transport in the liver, intestines, and across the blood-brain barrier (1,2,6).…”

mentioning

confidence: 99%

“…Owing to its role in MDR, several small molecule inhibitors of P-gp have been developed during the last four decades (2,17), but none have yet been approved for clinical use (18). In recent years, antibody-derived therapeutics have become increasingly popular because of their specific affinities and relatively high tolerance in humans.…”

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confidence: 99%

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Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain

Ward

Szewczyk²,

Grimard

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

236

224

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P-glycoprotein (P-gp) is one of the best-known mediators of drug efflux-based multidrug resistance in many cancers. This validated therapeutic target is a prototypic, plasma membrane resident ATPBinding Cassette transporter that pumps xenobiotic compounds out of cells. The large, polyspecific drug-binding pocket of P-gp recognizes a variety of structurally unrelated compounds. The transport of these drugs across the membrane is coincident with changes in the size and shape of this pocket during the course of the transport cycle. Here, we present the crystal structures of three inward-facing conformations of mouse P-gp derived from two different crystal forms. One structure has a nanobody bound to the C-terminal side of the first nucleotide-binding domain. This nanobody strongly inhibits the ATP hydrolysis activity of mouse Pgp by hindering the formation of a dimeric complex between the ATP-binding domains, which is essential for nucleotide hydrolysis. Together, these inward-facing conformational snapshots of P-gp demonstrate a range of flexibility exhibited by this transporter, which is likely an essential feature for the binding and transport of large, diverse substrates. The nanobody-bound structure also reveals a unique epitope on P-gp.

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confidence: 99%

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confidence: 99%

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Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain

Ward

Szewczyk²,

Grimard

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

236

224

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“…Since the depth of the cellular membrane is about 4 nm, half the P-gp is included in the phospholipid bilayer of the membrane. 55 P-gp is also found at intracellular membranes, 2,56,57 and is frequently observed in the nucleus 58-60 while also being described in the ER, 61 Golgi apparatus, 62,63 endosomes 64 and lysosomes 65 (organelles which are involved in its intracellular trafficking). 57 The presence of P-gp has also been described in mitochondria, where it may be involved in the protection of mitochondrial DNA.…”

Section: P-gp Synthesis Cellular Localization Expression and Functionmentioning

confidence: 99%

“…61,64 Therefore, it is important to better understand how P-gp is regulated, which seems to be a complex and highly controlled process. 2 Indeed, several signalling pathways and transcription factors have been described as being involved in the regulation of P-gp expression, such as Wnt=b-catenin, Ras=Raf, MAPK=ERK, p53, NF-jB and PKC. [71][72][73][74][75][76][77] Moreover, several extracellular stimuli such as heat shock, 78 UV radiation, 79 reactive oxygen species 80,81 and cytotoxic drugs 82,83 induce P-gp expression ( Fig.…”

Section: P-gp Synthesis Cellular Localization Expression and Functionmentioning

confidence: 99%

The network of P-glycoprotein and microRNAs interactions

et al. 2013

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Overexpression of P‐glycoprotein (P‐gp) contributes to the multidrug resistance (MDR) phenotype found in many cancer cells. P‐gp has been identified as a promising molecular target, although attempts to find successful therapies to counteract its function as a drug efflux pump have largely failed to date. Apart from its role in drug efflux, P‐gp may have other cellular functions such as being involved in apoptosis, and is found in various locations in the cell. Its expression is highly regulated, namely by microRNAs (miRNAs or miRs). In addition, P‐gp may regulate the expression of miRs in the cell. Furthermore, both P‐gp and miRs may be found in microvesicles or exosomes and may be transported to neighboring, drug‐sensitive cells. Here, we review this current issue together with recent evidence of this network of interactions between P‐gp and miRs.

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Drug Delivery Strategies for Combating Multiple Drug Resistance

Nichols

Bae

2013

Pharmaceutical Sciences Encyclopedia

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Although cancer research has been steady for the past 40 years, only modest gains have been observed in reducing cancer mortality rates, most significantly from prevention campaigns and less from drug therapy. This chapter outlines major mechanisms of drug resistance in tumors, emphasizing the contribution of each mechanism to the whole classification called multiple drug resistance (MDR), which is the simultaneous resistance to a wide range of drugs unrelated in structure or mechanism of action. For patients who demonstrate MDR markers, clinical outcomes tend to be poor. The chapter then samples innovative strategies to circumvent or overcome these resistance mechanisms, including the use of nanoparticles and new treatments that overcome drug delivery barriers.

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ABC Efflux Pump-Based Resistance to Chemotherapy Drugs

Cited by 546 publications

References 302 publications

Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain

Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain

The network of P-glycoprotein and microRNAs interactions

Drug Delivery Strategies for Combating Multiple Drug Resistance

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