ABC transporters in the balance: is there a role in multidrug resistance?1

2005 ◽  
Vol 33 (1) ◽  
pp. 241-245 ◽  
Author(s):  
O. Polgar ◽  
S.E. Bates
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Anticancer Agents ◽  
Abc Transporters ◽  
Drug Accumulation ◽  
Critical Studies ◽  
Multidrug Transporters ◽  
Consequent Reduction ◽  
And Function

Drug resistance can occur at several levels and is the major cause of treatment failure in oncology. The ABC (ATP-binding cassette) transporters, beginning with the discovery of P-gylcoprotein (Pgp) almost 30 years ago, have been intensively studied as potential mediators of drug resistance. Although we understand that drug resistance is almost certainly multifactorial, investigators have attempted to link anticancer drug resistance to overexpression of ABC transporters and the consequent reduction in drug accumulation. A body of evidence implicated Pgp as being important in clinical outcome; however, critical studies aimed at proving the hypothesis using Pgp inhibitors in clinical trials have to date failed. Identification of the MRP (multidrug resistance protein)/ABCC subfamily expanded the possible mechanisms of reduced drug accumulation, and the discovery of ABCG2 added a new chapter in these investigations. Correlative studies examining ABCG2 and the ABCC subfamily members in clinical drug resistance have been less avidly pursued, while basic molecular studies of structure and function have proceeded briskly. Recently, studies have focused on how single nucleotide polymorphism in multidrug transporters might affect the pharmacokinetics and pharmacodynamics of anticancer agents. These studies suggest an important role for ABC transporters in pharmacology, independent of the ultimate determination of their role in multidrug resistance.

Natural Product as Substrates of ABC Transporters: A Review

2021 ◽  
Vol 16 ◽  
Author(s):  
Xuan-Yu Chen ◽  
Jing-Quan Wang ◽  
Yuqi Yang ◽  
Jing Li ◽  
Zhe-Sheng Chen
Keyword(s):  
Drug Resistance ◽  
Natural Products ◽  
Multidrug Resistance ◽  
Abc Transporters ◽  
Chemotherapeutic Agents ◽  
Clinical Context ◽  
Daily Diet ◽  
Future Drug ◽  
Tumor Drugs ◽  
Anti Tumor Activity

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.

scholarly journals The Multidrug Resistance-Reversing Activity of a Novel Antimicrobial Peptide

Cancers ◽  
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.

Chalcone derivatives and their activities against drug-resistant cancers: An overview

2020 ◽  
Vol 20 ◽  
Author(s):  
Jiaqi Xiao ◽  
Meixiang Gao ◽  
Qiang Diao ◽  
Feng Gao
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Rational Design ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Chalcone Derivatives ◽  
Potential Activity ◽  
Defensive Mechanisms

: Drug resistance including multidrug resistance resulting from different defensive mechanisms in cancer cells is the leading cause of the failure about the cancer therapy, making it an urgent need to develop more effective anticancer agents. Chalcones, widely distributed in nature, could act on diverse enzymes and receptors in cancer cells. Accordingly, chalcone derivatives possess potential activity against various cancers including drug-resistant even multidrug-resistant cancer. This review outlines the recent development of chalcone derivatives with potential activity against drug-resistant cancers covering articles published between 2010 and 2020, so as to facilitate further rational design of more effective candidate.

P38 Study of drug resistance in patients with acute leukaemia: determination of mRNA ABC-transporters and apoptotic proteins

2008 ◽  
Vol 6 (3) ◽  
pp. 54
Author(s):  
J. Hatok ◽  
J. Chudej ◽  
P. Chudy ◽  
L. Bartosova ◽  
J. Jurecekova ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Abc Transporters ◽  
Acute Leukaemia ◽  
Apoptotic Proteins

scholarly journals The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 949
Author(s):  
Mahendra Jadhao ◽  
Eing-Mei Tsai ◽  
Ho-Chun Yang ◽  
Yih-Fung Chen ◽  
Shih-Shin Liang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Breast Cancer Cells ◽  
Acquired Drug Resistance ◽  
Intracellular Ros ◽  
Dehp Exposure

The characteristics of phthalates had been thought to be similar to endocrine disruptors, which increases cancer risk. The role of phthalates in acquired drug resistance remains unclear. In this study, we investigated the effect of di-(2-ethylhexyl) phthalate (DEHP) on acquired drug resistance in breast cancer. MCF7 and MDA-MB-231 breast cancer cells were exposed to long-term physiological concentration of DEHP for more than three months. Long-exposure DEHP permanently attenuated the anti-proliferative effect of doxorubicin with estrogen receptor-independent activity even after withdrawal of DEHP. Long term DEHP exposure significantly reduced ROS (O2−) level in MDA-MB-231 cells while increased in MCF7 cells. ATP-binding cassette (ABC) transporters possess a widely recognized mechanism of drug resistance and are considered a target for drug therapy. Upregulation of ABC family proteins, ABCB-1 and ABCC-1 observed in DEHP-exposed clones compared to doxorubicin-resistant (DoxR) and parental MDA-MB-231 cells. A viability assay showed enhanced multidrug resistance in DEHP-exposed clones against Dox, topotecan, and irinotecan. Inhibition of ABC transporters with tariquidar, enhanced drug cytotoxicity through increased drug accumulation reversing acquired multidrug resistance in MDA-MB-231 breast cancer cells. Tariquidar enhanced Dox cytotoxicity by increasing intracellular ROS production leading to caspase-3 mediated apoptosis. Activation of PI3K/Akt signaling enhanced proliferation and growth of DEHP-exposed MDA-MB-231 cells. Overall, long-term DEHP exposure resulted in acquired multidrug resistance by upregulating ABCB-1 and ABCC1; apart from proliferation PI3K/Akt may be responsible for acquired drug resistance through ABC transporter upregulation. Targeting ABCB1 and ABCC1 with tariquidar may be a promising strategy for reversing the acquired multidrug resistance of triple-negative breast cancer cells.

Structure and function of human ABC transporters involved in multidrug resistance of cancer

2000 ◽  
Vol 28 (5) ◽  
pp. A143-A143
Author(s):  
B. Sarkadi ◽  
É. Bakos ◽  
G. Szakács ◽  
K. Szabó ◽  
A. Váradi
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Structure And Function ◽  
And Function

scholarly journals Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy

2018 ◽  
Vol 19 (8) ◽  
pp. 2256 ◽  
Author(s):  
Antoni Domagala ◽  
Klaudyna Fidyt ◽  
Malgorzata Bobrowicz ◽  
Joanna Stachura ◽  
Kacper Szczygiel ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Treatment Resistance ◽  
Metastatic Potential ◽  
Dependent Cell ◽  
And Function

Lysosomes are conservative organelles with an indispensable role in cellular degradation and the recycling of macromolecules. However, in light of recent findings, it has emerged that the role of lysosomes in cancer cells extends far beyond cellular catabolism and includes a variety of cellular pathways, such as proliferation, metastatic potential, and drug resistance. It has been well described that malignant transformation leads to alterations in lysosomal structure and function, which, paradoxically, renders cancer cells more sensitive to lysosomal destabilization. Furthermore, lysosomes are implicated in the regulation and execution of cell death in response to diverse stimuli and it has been shown that lysosome-dependent cell death can be utilized to overcome apoptosis and drug resistance. Thus, the purpose of this review is to characterize the role of lysosome in cancer therapy and to describe how these organelles impact treatment resistance. We summarized the characteristics of typical inducers of lysosomal cell death, which exert its function primarily via alterations in the lysosomal compartment. The review also presents other anticancer agents with the predominant mechanism of action different from lysosomal destabilization, the activity of which is influenced by lysosomal signaling, including classical chemotherapeutics, kinase inhibitors, monoclonal antibodies, as well as photodynamic therapy.

The multidrug transporter Pdr5: a molecular diode?

2011 ◽  
Vol 392 (1-2) ◽  
Author(s):  
Rakeshkumar P. Gupta ◽  
Petra Kueppers ◽  
Lutz Schmitt ◽  
Robert Ernst
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Abc Transporters ◽  
Multidrug Transporter ◽  
Binding Domains ◽  
Molecular Diode ◽  
The Family ◽  
Cellular Detoxification ◽  
Functional Relevance

Abstract A subset of the family of ATP-binding cassette (ABC) transporters has been in focus owing to their involvement in conferring multidrug resistance in cancer cells and among immune compromised individuals. Saccharomyces cerevisiae is protected against xenobiotics by similar machineries that are part of the pleitropic drug resistance (PDR) network. The ABC transporter Pdr5 is an important member of this PDR network in yeast and is involved in cellular detoxification by the efflux of a wide variety of drugs and substrates. In this review, we focus on the aspects of detergent effects and the degeneracy in conserved sequences that is observed in the nucleotide binding domains of Pdr5 and discuss their functional relevance.

scholarly journals The Role of the Actin Cytoskeleton and Lipid Rafts in the Localization and Function of the ABCC1 Transporter

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Jan Willem Kok ◽  
Karin Klappe ◽  
Ina Hummel
Keyword(s):  
Multidrug Resistance ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Abc Transporters ◽  
Cortical Actin ◽  
Resistance Development ◽  
Specific Localization ◽  
Drug Efflux Pumps ◽  
And Function

ATP-binding cassette (ABC) transporters are known to be important factors in multidrug resistance of tumor cells. Lipid rafts have been implicated in their localization in the plasma membrane, where they function as drug efflux pumps. This specific localization in rafts may support the activity of ABC/Abc transporters. This raises questions regarding the nature and composition of the lipid rafts that harbor ABC/Abc transporters and the dependence of ABC/Abc transporters—concerning their localization and activity—on lipid raft constituents. Here we review our work of the past 10 years aimed at evaluating whether ABC/Abc transporters are dependent on a particular membrane environment for their function. What is the nature of this membrane environment and which of the lipid raft constituents are important for this dependency? It turns out that cortical actin is of major importance for stabilizing the localization and function of the ABC/Abc transporter, provided it is localized in an actin-dependent subtype of lipid rafts, as is the case for human ABCC1/multidrug resistance-related protein 1 (MRP1) and rodent Abcc1/Mrp1 but not human ABCB1/P-glycoprotein (PGP). On the other hand, sphingolipids do not appear to be modulators of ABCC1/MRP1 (or Abcc1/Mrp1), even though they are coregulated during drug resistance development.

scholarly journals Multiple-drug-resistance phenomenon in the yeast Saccharomyces cerevisiae: involvement of two hexose transporters.

1997 ◽  
Vol 17 (9) ◽  
pp. 5453-5460 ◽  
Author(s):  
A Nourani ◽  
M Wesolowski-Louvel ◽  
T Delaveau ◽  
C Jacq ◽  
A Delahodde
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Abc Transporters ◽  
Multiple Drug Resistance ◽  
Kluyveromyces Lactis ◽  
Major Facilitator Superfamily ◽  
Multiple Drug ◽  
Yeast Saccharomyces Cerevisiae ◽  
Hexose Transporters

In the yeast Saccharomyces cerevisiae, multidrug resistance to unrelated chemicals can result from overexpression of ATP-binding cassette (ABC) transporters such as Pdr5p, Snq2p, and Yor1p. Expression of these genes is under the control of two homologous zinc finger-containing transcription regulators, Pdr1p and Pdr3p. Here, we describe the isolation, by an in vivo screen, of two new Pdr1p-Pdr3p target genes: HXT11 and HXT9. HXT11 and HXT9, encoding nearly identical proteins, have a high degree of identity to monosaccharide transporters of the major facilitator superfamily (MFS). In this study, we show that the HXT11 product, which allows glucose uptake in a glucose permease mutant (rag1) strain of Kluyveromyces lactis, is also involved in the pleiotropic drug resistance process. Loss of HXT11 and/or HXT9 confers cycloheximide, sulfomethuron methyl, and 4-NQO (4-nitroquinoline-N-oxide) resistance. Conversely, HXT11 overexpression increases sensitivity to these drugs in the wild-type strain, an effect which is more pronounced in a strain having both PDR1 and PDR3 deleted. These data show that the two putative hexose transporters Hxt11p and Hxt9p are transcriptionally regulated by the transcription factors Pdr1p and Pdr3p, which are known to regulate the production of ABC transporters required for drug resistance in yeast. We thus demonstrate the existence of genetic interactions between genes coding for two classes of transporters (ABC and MFS) to control the multidrug resistance process.

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