SOLVING THE PROBLEM OF MULTIDRUG RESISTANCE: ABC TRANSPORTERS IN CLINICAL ONCOLOGY

Background: To date, many compounds extracting from natural products have anti-tumor activity, such as citronellol, ellagitannin-containing pomegranate extract, etc. Evidence from clinical context shows that multidrug resistance is an obstacle that impedes the effectiveness of natural products, such as chemotherapeutic agents paclitaxel and vincristine. Overexpression of ATP-Binding Cassette (ABC) transporters is the leading cause of MDR. Therefore, it is crucial to investigate whether these natural products are substrates of MDR-associated ABC transporters, which may benefit the development of their clinical usage. Objective: This review summarizes the latest insight on natural products possessing substrate profile and analyzed some possible regularity to provide direction for future drug discovery. Conclusion: The anti-tumor effects of natural products are constantly being explored, but the drug resistance issues cannot be ignored, which limits their prospects as anti-tumor drugs to a certain extent. At the same time, some natural products are taken as a daily diet, and their possible role in increasing the drug resistance of the substrate should arouse the attention of clinical cancer patients.

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The Multidrug Resistance-Reversing Activity of a Novel Antimicrobial Peptide

Cancers ◽

10.3390/cancers12071963 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1963

Author(s):

Qiu-Xu Teng ◽

Xiaofang Luo ◽

Zi-Ning Lei ◽

Jing-Quan Wang ◽

John Wurpel ◽

...

Keyword(s):

Multidrug Resistance ◽

Antimicrobial Peptides ◽

Anticancer Drugs ◽

Anticancer Agents ◽

Abc Transporters ◽

Intracellular Accumulation ◽

The Past ◽

Novel Strategy ◽

New Generation ◽

Abcb1 Transporter

The overexpression of ATP-binding cassette (ABC) transporters is a common cause of multidrug resistance (MDR) in cancers. The intracellular drug concentration of cancer cells can be decreased relative to their normal cell counterparts due to increased expression of ABC transporters acting as efflux pumps of anticancer drugs. Over the past decades, antimicrobial peptides have been investigated as a new generation of anticancer drugs and some of them were reported to have interactions with ABC transporters. In this article, we investigated several novel antimicrobial peptides to see if they could sensitize ABCB1-overexpressing cells to the anticancer drugs paclitaxel and doxorubicin, which are transported by ABCB1. It was found that peptide XH-14C increased the intracellular accumulation of ABCB1 substrate paclitaxel, which demonstrated that XH-14C could reverse ABCB1-mediated MDR. Furthermore, XH-14C could stimulate the ATPase activity of ABCB1 and the molecular dynamic simulation revealed a stable binding pose of XH-14C-ABCB1 complex. There was no change on the expression level or the location of ABCB1 transporter with the treatment of XH-14C. Our results suggest that XH-14C in combination with conventional anticancer agents could be used as a novel strategy for cancer treatment.

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Hedgehog signaling promotes multidrug resistance by regulation of ABC transporters in oral squamous cell carcinoma

Journal of Oral Pathology and Medicine ◽

10.1111/jop.13050 ◽

2020 ◽

Vol 49 (9) ◽

pp. 897-906

Author(s):

Xiangwan Lu ◽

Zhanghao Wang ◽

Hongxing Huang ◽

Hua Wang

Keyword(s):

Squamous Cell Carcinoma ◽

Multidrug Resistance ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Abc Transporters ◽

Hedgehog Signaling

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Human ATP-Binding Cassette Transporter TaqMan Low-Density Array: Analysis of Macrophage Differentiation and Foam Cell Formation

Clinical Chemistry ◽

10.1373/clinchem.2005.059774 ◽

2006 ◽

Vol 52 (2) ◽

pp. 310-313 ◽

Cited By ~ 39

Author(s):

Thomas Langmann ◽

Richard Mauerer ◽

Gerd Schmitz

Keyword(s):

Multidrug Resistance ◽

Abc Transporter ◽

Abc Transporters ◽

Metabolic Regulation ◽

Foam Cell ◽

Expression Patterns ◽

Foam Cell Formation ◽

Atp Binding ◽

Low Density ◽

Atp Binding Cassette

Abstract Background: ATP-binding cassette (ABC) transporters cause various diseases and regulate many physiologic processes, such as lipid homeostasis, iron transport, and immune mechanisms. Several ABC transporters are involved in bile acid, phospholipid, and sterol transport, and their expression is itself controlled by lipids. In addition, ABC proteins mediate drug export in tumor cells and promote the development of multidrug resistance. Methods: We created an ABC Transporter TaqMan Low-Density Array based on an Applied Biosystems 7900HT Micro Fluidic Card. We used a 2-μL reaction well with 2 ng of sample. To evaluate this method for lipidomic research and to characterize expression patterns of ABC transporters in cells relevant for atherosclerosis research, we monitored mRNA expression in human primary monocytes, in vitro–differentiated macrophages, and cells stimulated with the liver-X-receptor and retinoid-X-receptor agonists T0901317 and 9-cis retinoic acid, mimicking sterol loading. Results: The method enabled simultaneous analysis of 47 human ABC transporters and the reference gene 18S rRNA in 2 replicates of 4 samples per run. Conclusions: The new system uses only 2 ng of sample and small volumes of reagent, and the precaptured primers and probes avoided labor-intensive pipetting steps. The ABC Transporter TaqMan Low-Density Array may be a useful tool to monitor dysregulated ABC transporter mRNA profiles in human lipid disorders and cancer-related multidrug resistance and to analyze the pharmacologic and metabolic regulation of ABC transporter expression important for drug development in large-scale screening approaches.

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Multidrug Resistance Mediated by MDR-ABC Transporters

Drug Resistance in Cancer Cells ◽

10.1007/978-0-387-89445-4_1 ◽

2009 ◽

pp. 1-20 ◽

Cited By ~ 2

Author(s):

Gergely Szakács ◽

Kenneth Kin Wah ◽

Orsolya Polgár ◽

Robert W. Robey ◽

Susan E. Bates

Keyword(s):

Multidrug Resistance ◽

Abc Transporters

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

BioMolecular Concepts ◽

10.1515/bmc-2012-0006 ◽

2012 ◽

Vol 3 (4) ◽

pp. 319-331 ◽

Cited By ~ 3

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.

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

Canadian Journal of Zoology ◽

10.1139/cjz-2015-0011 ◽

2015 ◽

Vol 93 (7) ◽

pp. 567-578 ◽

Cited By ~ 4

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.

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