scholarly journals The controversial role of ABC transporters in clinical oncology

2011 ◽  
Vol 50 ◽  
pp. 209-232 ◽  
Author(s):  
Akina Tamaki ◽  
Caterina Ierano ◽  
Gergely Szakacs ◽  
Robert W. Robey ◽  
Susan E. Bates
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Clinical Intervention ◽  
Cancer Resistance ◽  
P Glycoprotein ◽  
Cancer Types ◽  
Resistance Protein ◽  
Chemotherapy Efficacy ◽  
Transporter Expression

The phenomenon of multidrug resistance in cancer is often associated with the overexpression of the ABC (ATP-binding cassette) transporters Pgp (P-glycoprotein) (ABCB1), MRP1 (multidrug resistance-associated protein 1) (ABCC1) and ABCG2 [BCRP (breast cancer resistance protein)]. Since the discovery of Pgp over 35 years ago, studies have convincingly linked ABC transporter expression to poor outcome in several cancer types, leading to the development of transporter inhibitors. Three generations of inhibitors later, we are still no closer to validating the ‘Pgp hypothesis’, the idea that increased chemotherapy efficacy can be achieved by inhibition of transporter-mediated efflux. In this chapter, we highlight the difficulties and past failures encountered in the development of clinical inhibitors of ABC transporters. We discuss the challenges that remain in our effort to exploit decades of work on ABC transporters in oncology. In learning from past mistakes, it is hoped that ABC transporters can be developed as targets for clinical intervention.

scholarly journals Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3364 ◽  
Author(s):  
Bruno M. F. Gonçalves ◽  
David S. P. Cardoso ◽  
Maria-José U. Ferreira
Keyword(s):  
Multidrug Resistance ◽  
Natural Product ◽  
Abc Transporter ◽  
Efflux Pumps ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Multidrug Resistance Protein 1 ◽  
P Glycoprotein ◽  
Resistance Protein

Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

scholarly journals Multidrug resistance-associated ABC transporters – too much of one thing, good for nothing

2012 ◽  
Vol 3 (4) ◽  
pp. 319-331 ◽  
Author(s):  
Jirina Prochazkova ◽  
Martina Lanova ◽  
Jiri Pachernik
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Family Members ◽  
Atp Binding ◽  
Detailed Mechanism ◽  
P Glycoprotein ◽  
The Future ◽  
Good For

AbstractOverexpression of ATP-binding cassette (ABC) transporters in cancer cells results in multidrug resistance (MDR) which leads to unsuccessful chemotherapy. The most important MDR-associated members of ABC superfamily are ABC B1/P-glycoprotein/MDR1, ABC C1/multidrug resistance associated protein 1 (MRP1), and ABC G2/BCRP. This study is not only focused on function, substrates, and localization of these popular proteins but also on other ABC C family members such as ABC C2–6/MRP2-6 and ABC C7/CFTR. Current research is mainly oriented on the cancer-promoting role of these proteins, but important lessons could also be learned from the physiological roles of these proteins or from polymorphisms affecting their function. Thorough knowledge of structure and detailed mechanism of efflux can aid in the discovery of new chemotherapy targets in the future. Although the best way on how to deal with MDR would be to prevent its development, we describe some new promising strategies on how to conquer both inherited and induced MDRs.

Two novel multidrug resistance associated protein (MRP/ABCC) from the Mediterranean mussel (Mytilus galloprovincialis): characterization and expression patterns in detoxifying tissues

2015 ◽  
Vol 93 (7) ◽  
pp. 567-578 ◽  
Author(s):  
V. Lozano ◽  
R. Martínez-Escauriaza ◽  
M.L. Pérez-Parallé ◽  
A.J. Pazos ◽  
J.L. Sánchez
Keyword(s):  
Multidrug Resistance ◽  
Digestive Gland ◽  
Okadaic Acid ◽  
Abc Transporters ◽  
Mytilus Galloprovincialis ◽  
Expression Patterns ◽  
Cancer Resistance ◽  
Mediterranean Mussel ◽  
The Mediterranean

Multidrug resistance associated proteins (MRP) belong to the ABCC branch of the ABC transporters. The MRP together with P-gp (P-glycoprotein; MDR1; ABCB1) and BCRP (breast cancer resistance protein; ABCG2) confer multixenobiotic resistance (MXR) in marine vertebrates. In aquatic invertebrates, little is known about the presence and role of these ABC transporters. The ABC transporters play an important role in the absorption, distribution, and excretion of drugs, xenobiotics, and endogenous compounds and are predominantly expressed in excretory organs. In the present study, we identified and characterized two MRP/ABCC transporters (mrp1 and mrp2) from the Mediterranean mussel (Mytilus galloprovincialis Lamarck, 1819). The two cDNAs finally obtained were 4648 bp for mrp1 and 5065 bp for mrp2 with open reading frames of 1500 and 1524 residues, respectively. Analysis of the amino acid sequences revealed the structural organization of ABC transporters with the typical and highly conserved motifs. The expression levels of these genes revealed that the highest expression of mrp1 and mrp2 genes was found in the digestive gland followed by gills, and the lowest expression of the three tissues was detected in the mantle. The expression of these genes was also studied in mussels naturally contaminated with okadaic acid (from a bloom of Dinophysis acuminata Claparède and Lachmann, 1859). The overexpression of mrp2 in the digestive gland suggests that this gene is involved in the process of detoxification of okadaic acid in M. galloprovincilais. These expression patterns agree with the suggested role of these genes in the protection against endogenous or exogenous compounds in aquatic organisms.

Identification of ABC transporters inSarcoptes scabiei

Parasitology ◽  
2006 ◽  
Vol 132 (6) ◽  
pp. 883-892 ◽  
Author(s):  
K. E. MOUNSEY ◽  
D. C. HOLT ◽  
J. McCARTHY ◽  
S. F. WALTON
Keyword(s):  
Abc Transporters ◽  
Potential Role ◽  
Sarcoptes Scabiei ◽  
Degenerate Pcr ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Multiple Treatments ◽  
Crusted Scabies

We have identified and partially sequenced 8 ABC transporters from an EST dataset ofSarcoptes scabieivar.hominis, the causative agent of scabies. Analysis confirmed that most of the known ABC subfamilies are represented in the EST dataset including several members of the multidrug resistance protein subfamily (ABC-C). Although P-glycoprotein (ABC-B) sequences were not found in the EST dataset, a partial P-glycoprotein sequence was subsequently obtained using a degenerate PCR strategy and library screening. Thus a total of 9 potentialS. scabieiABC transporters representing the subfamilies A, B, C, E, F and H have been identified. Ivermectin is currently used in the treatment of hyper-infested (crusted) scabies, and has also been identified as a potentially effective acaricide for mass treatment programmes in scabies-endemic communities. The observation of clinical andin vitroivermectin resistance in 2 crusted scabies patients who received multiple treatments has raised serious concerns regarding the sustainability of such programmes. One possible mechanism for ivermectin resistance is through ABC transporters such as P-glycoprotein. This work forms an important foundation for further studies to elucidate the potential role of ABC transporters in ivermectin resistance ofS. scabiei.

scholarly journals The role of dietary flavonoids for modulation of ATP binding cassette transporter mediated multidrug resistance

eFood ◽  
2021 ◽  
Author(s):  
Hui Teng ◽  
Hongting Deng ◽  
Yuanju He ◽  
Qiyan Lv ◽  
Lei Chen
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Systemic Circulation ◽  
Atp Binding ◽  
Cancer Resistance ◽  
Associated Proteins ◽  
Food Toxin ◽  
Atp Binding Cassette

Flavonoids are widely existing compounds with enormous pharmacological effects from food and medicine. However, the low bioavailability in intestinal absorption and metabolism limits their clinical application. Intestinal efflux ABC (ATP binding cassette) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), act as "pumping doors" to regulate the efflux of flavonoids from intestinal epithelial cells into the intestinal cavity or the systemic circulation. The present review describes the critical effect of ABC transporters involved in the efflux of flavonoids which depend on its efflux direction. And the role of flavonoids for modulation of intestinal ABC transporters was emphasized and several examples were given. We summarized that the resistance effect of flavonoid-mediated multidrug on ABC transporters may influence the bioavailability of drugs, bioactive ingredients and/or toxic compounds upon dietary uptake. Meanwhile, flavonoids functionalized as reversing agents of the ABC transporter may be an important mechanism for unexpected food-drug, food-toxin or food-food interactions. The overview also indicates that elucidation of the action and mechanism of the intestinal metabolic enzymes-efflux transporters coupling will lay a foundation for improving the bioavailability of flavonoids <i>in vivo</i> and increasing their clinical efficacy.

Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues

2002 ◽  
Vol 361 (3) ◽  
pp. 497-503 ◽  
Author(s):  
Liqi LAI ◽  
Theresa M. C. TAN
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Transmembrane Domain ◽  
The Other ◽  
Nucleoside Analogues ◽  
Intracellular Camp ◽  
Multidrug Resistance Protein ◽  
Purine Analogues ◽  
Resistance Protein

Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the MRP subfamily, which in turn is a member of the superfamily of ATP-binding-cassette (ABC) transporters. Within the MRP subfamily, ABCC4, ABCC5 (MRP5), ABCC11 (MRP8) and ABCC12 (MRP9) have similar predicted membrane topologies. All lack the additional transmembrane domain, TMD0, which is present in the other MRPs. Using cells stably overexpressing ABCC4, this study shows that ABCC4 exports GSH. ABCC4 also facilitates the efflux of cAMP. Depletion of intracellular GSH with dl-buthionine-(S,R)-sulphoximine led to decreased export of cAMP and a corresponding increase in intracellular cAMP was observed. ABCC4 also mediates resistance to purine analogues 9-(2-phosphonylmethoxyethyl)-adenine and 6-thioguanine. This resistance can be reversed by the presence of dl-buthionine-(S,R)-sulphoximine. We conclude that as well as nucleotide and nucleoside analogues, ABCC4 can mediate the export of GSH. In addition, GSH plays an important role in the function of ABCC4. Depletion of intracellular GSH adversely affects the export of cAMP by ABCC4. Resistance to nucleoside analogues is also adversely affected by depletion of cellular GSH.

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