The Role of SLC and ABC Transporters in Anti-cancer Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (30 October 2022) | Viewed by 14464

Special Issue Editor


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Guest Editor
Department of Pharmaceutical Technology and Biotechnology, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 329, D-69120 Heidelberg, Germany
Interests: pharmacokinetics; transporters; analytical chemistry; drug delivery; drug targeting; transporter mediated anticancer drug resistance; blood-brain barrier

Special Issue Information

Dear Colleagues,

Solute carriers (SLCs) and ATP-binding cassette family (ABC) transporters play crucial roles in the absorption, disposition, and elimination of many anti-cancer drugs. Transporter-mediated drug resistance is one of the main reasons for the limited efficacy of cancer drug therapy. In addition, many SLC and ABC transporters have been acknowledged as important targets for anti-cancer drug development. In the past decades, our knowledge about the structure, expression, substrate specificity, and function of SLCs and ABCs in cancer has increased considerably. These improvements have opened new avenues in the field of drug transport across cancer cell membrane barriers.

This Special Issue will provide readers with an overview of the current advances in the field of transporter-mediated drug delivery in cancer and a fundamental understanding of the role of SLCs and ABCs in drug delivery to tumors

Dr. Mikko Gynther
Guest Editor

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Keywords

  • membrane transporters
  • drug delivery
  • solute carriers
  • ABC transporters
  • targeted delivery

Published Papers (6 papers)

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Research

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17 pages, 4117 KiB  
Article
Characterization of Potent ABCG2 Inhibitor Derived from Chromone: From the Mechanism of Inhibition to Human Extracellular Vesicles for Drug Delivery
by Glaucio Valdameri, Diogo Henrique Kita, Julia de Paula Dutra, Diego Lima Gomes, Arun Kumar Tonduru, Thales Kronenberger, Bruno Gavinho, Izadora Volpato Rossi, Mariana Mazetto de Carvalho, Basile Pérès, Ingrid Fatima Zattoni, Fabiane Gomes de Moraes Rego, Geraldo Picheth, Rilton Alves de Freitas, Antti Poso, Suresh V. Ambudkar, Marcel I. Ramirez, Ahcène Boumendjel and Vivian Rotuno Moure
Pharmaceutics 2023, 15(4), 1259; https://doi.org/10.3390/pharmaceutics15041259 - 17 Apr 2023
Cited by 1 | Viewed by 1264
Abstract
Inhibition of ABC transporters is a promising approach to overcome multidrug resistance in cancer. Herein, we report the characterization of a potent ABCG2 inhibitor, namely, chromone 4a (C4a). Molecular docking and in vitro assays using ABCG2 and P-glycoprotein (P-gp) expressing membrane [...] Read more.
Inhibition of ABC transporters is a promising approach to overcome multidrug resistance in cancer. Herein, we report the characterization of a potent ABCG2 inhibitor, namely, chromone 4a (C4a). Molecular docking and in vitro assays using ABCG2 and P-glycoprotein (P-gp) expressing membrane vesicles of insect cells revealed that C4a interacts with both transporters, while showing selectivity toward ABCG2 using cell-based transport assays. C4a inhibited the ABCG2-mediated efflux of different substrates and molecular dynamic simulations demonstrated that C4a binds in the Ko143-binding pocket. Liposomes and extracellular vesicles (EVs) of Giardia intestinalis and human blood were used to successfully bypass the poor water solubility and delivery of C4a as assessed by inhibition of the ABCG2 function. Human blood EVs also promoted delivery of the well-known P-gp inhibitor, elacridar. Here, for the first time, we demonstrated the potential use of plasma circulating EVs for drug delivery of hydrophobic drugs targeting membrane proteins. Full article
(This article belongs to the Special Issue The Role of SLC and ABC Transporters in Anti-cancer Drug Delivery)
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28 pages, 9250 KiB  
Article
Sorafenib Chemosensitization by Caryophyllane Sesquiterpenes in Liver, Biliary, and Pancreatic Cancer Cells: The Role of STAT3/ABC Transporter Axis
by Silvia Di Giacomo, Marco Gullì, Roberta Facchinetti, Marco Minacori, Romina Mancinelli, Ester Percaccio, Caterina Scuderi, Margherita Eufemi and Antonella Di Sotto
Pharmaceutics 2022, 14(6), 1264; https://doi.org/10.3390/pharmaceutics14061264 - 14 Jun 2022
Cited by 8 | Viewed by 2264
Abstract
A combination of anticancer drugs and chemosensitizing agents has been approached as a promising strategy to potentiate chemotherapy and reduce toxicity in aggressive and chemoresistant cancers, like hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and pancreatic ductal adenocarcinoma (PDAC). In the present study, the ability [...] Read more.
A combination of anticancer drugs and chemosensitizing agents has been approached as a promising strategy to potentiate chemotherapy and reduce toxicity in aggressive and chemoresistant cancers, like hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and pancreatic ductal adenocarcinoma (PDAC). In the present study, the ability of caryophyllane sesquiterpenes to potentiate sorafenib efficacy was studied in HCC, CCA, and PDAC cell models, focusing on the modulation of STAT3 signaling and ABC transporters; tolerability studies in normal cells were also performed. Results showed that the combination of sorafenib and caryophyllane sesquiterpenes synergized the anticancer drug, especially in pancreatic Bx-PC3 adenocarcinoma cells; a similar trend, although with lower efficacy, was found for the standard ABC transporter inhibitors. Synergistic effects were associated with a modulation of MDR1 (or Pgp) and MRP transporters, both at gene and protein level; moreover, activation of STAT3 cascade and cell migration appeared significantly affected, suggesting that the STAT3/ABC-transporters axis finely regulated efficacy and chemoresistance to sorafenib, thus appearing as a suitable target to overcome drawbacks of sorafenib-based chemotherapy in hepato-biliary-pancreatic cancers. Present findings strengthen the interest in caryophyllane sesquiterpenes as chemosensitizing and chemopreventive agents and contribute to clarifying drug resistance mechanisms in HCC, CCA, and PDAC cancers and to developing possible novel therapeutic strategies. Full article
(This article belongs to the Special Issue The Role of SLC and ABC Transporters in Anti-cancer Drug Delivery)
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19 pages, 6899 KiB  
Article
DNA Copy Number Aberrations and Expression of ABC Transporter Genes in Breast Tumour: Correlation with the Effect of Neoadjuvant Chemotherapy and Prognosis of the Disease
by Matvey M. Tsyganov, Marina K. Ibragimova, Kseniya A. Gaptulbarova, Irina A. Tsydenova, Daria S. Dolgasheva, Evgeniy Y. Garbukov, Anastasia A. Frolova, Elena M. Slonimskaya and Nikolai V. Litvyakov
Pharmaceutics 2022, 14(5), 948; https://doi.org/10.3390/pharmaceutics14050948 - 27 Apr 2022
Cited by 4 | Viewed by 1580
Abstract
One of the important reasons for the ineffectiveness of chemotherapy in breast cancer (BC) is considered to be the formation of a multidrug resistance phenotype in tumour cells, which is caused by the expression of energy-dependent ABC transporters. The aim of this work [...] Read more.
One of the important reasons for the ineffectiveness of chemotherapy in breast cancer (BC) is considered to be the formation of a multidrug resistance phenotype in tumour cells, which is caused by the expression of energy-dependent ABC transporters. The aim of this work was to assess chromosomal aberrations and the level of transcripts of all 49 known ABC transporter genes in breast tumours. Materials and Methods. The study included 129 patients with breast cancer. A microarray study of all tumour samples was carried out on microchips. Results. This study established that the presence of a deletion in genes ABCB1, ABCB4, ABCB8, ABCC7, ABCC11, ABCC12, ABCF2, and ABCG4 is associated with an objective response to treatment (p ≤ 0.05). A decrease in the expression of genes was associated with a good response to chemotherapy, whereas an increase in expression caused the progression and stabilization of the tumour. Analysis of metastatic-free survival rates showed that the presence of ABCB1/4 and ABCC1/6 deletions was associated with 100% survival (log-rank test p = 0.01 and p = 0.03). Conclusions. The study showed that the aberrant state of ABC transporter genes, as well as a decrease in the expression of these genes, is a predictor of the effectiveness of therapeutic treatment and a potential prognostic marker of metastatic survival. Full article
(This article belongs to the Special Issue The Role of SLC and ABC Transporters in Anti-cancer Drug Delivery)
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17 pages, 2445 KiB  
Article
Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity
by Kuljeet Singh, Szabolcs Tarapcsák, Zsuzsanna Gyöngy, Zsuzsanna Ritter, Gyula Batta, Rosevalentine Bosire, Judit Remenyik and Katalin Goda
Pharmaceutics 2021, 13(12), 2062; https://doi.org/10.3390/pharmaceutics13122062 - 02 Dec 2021
Cited by 8 | Viewed by 2852
Abstract
P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and [...] Read more.
P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and excretion of many drugs. Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) are overexpressed in nearly all cancers and cancer stem cells by which cancer cells become resistant against many drugs. Thus, Pgp inhibition might be a strategy for fighting against drug-resistant cancer cells. Previous studies have shown that certain polyphenols interact with human Pgp. We tested the effect of 15 polyphenols of sour cherry origin on the basal and verapamil-stimulated ATPase activity of Pgp, calcein-AM and daunorubicin transport as well as on the conformation of Pgp using the conformation sensitive UIC2 mAb. We found that quercetin, quercetin-3-glucoside, narcissoside and ellagic acid inhibited the ATPase activity of Pgp and increased the accumulation of calcein and daunorubicin by Pgp-positive cells. Cyanidin-3O-sophoroside, catechin, naringenin, kuromanin and caffeic acid increased the ATPase activity of Pgp, while they had only a weaker effect on the intracellular accumulation of fluorescent Pgp substrates. Several tested polyphenols including epicatechin, trans-ferulic acid, oenin, malvin and chlorogenic acid were ineffective in all assays applied. Interestingly, catechin and epicatechin behave differently, although they are stereoisomers. We also investigated the effect of quercetin, naringenin and ellagic acid added in combination with verapamil on the transport activity of Pgp. In these experiments, we found that the transport inhibitory effect of the tested polyphenols and verapamil was additive or synergistic. Generally, our data demonstrate diverse interactions of the tested polyphenols with Pgp. Our results also call attention to the potential risks of drug–drug interactions (DDIs) associated with the consumption of dietary polyphenols concurrently with chemotherapy treatment involving Pgp substrate/inhibitor drugs. Full article
(This article belongs to the Special Issue The Role of SLC and ABC Transporters in Anti-cancer Drug Delivery)
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Review

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39 pages, 1762 KiB  
Review
The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy
by Elena Puris, Gert Fricker and Mikko Gynther
Pharmaceutics 2023, 15(2), 364; https://doi.org/10.3390/pharmaceutics15020364 - 21 Jan 2023
Cited by 4 | Viewed by 2268
Abstract
Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters [...] Read more.
Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters can be down-regulated in cancer cells, which limits the uptake of drugs into the tumor cells, resulting in the inefficiency of the drug therapy. In this review, we summarize the current understanding of low-SLC-transporter-expression-mediated drug resistance in different types of cancers. Recent advances in SLC-transporter-targeting strategies include the development of transporter-utilizing prodrugs and nanocarriers and the modulation of SLC transporter expression in cancer cells. These strategies will play an important role in the future development of anticancer drug therapies by enabling the efficient delivery of drugs into cancer cells. Full article
(This article belongs to the Special Issue The Role of SLC and ABC Transporters in Anti-cancer Drug Delivery)
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Other

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31 pages, 922 KiB  
Systematic Review
Systematic Review of Pharmacogenetics of ABC and SLC Transporter Genes in Acute Myeloid Leukemia
by Juan Eduardo Megías-Vericat, David Martínez-Cuadrón, Antonio Solana-Altabella, José Luis Poveda and Pau Montesinos
Pharmaceutics 2022, 14(4), 878; https://doi.org/10.3390/pharmaceutics14040878 - 17 Apr 2022
Cited by 6 | Viewed by 2709
Abstract
Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in SLC and ABC could produce interindividual differences in clinical outcomes. A systematic [...] Read more.
Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in SLC and ABC could produce interindividual differences in clinical outcomes. A systematic review was performed to evaluate the influence of SLC and ABC polymorphisms and their combinations on efficacy and safety in AML cohorts. Anthracycline intake was especially influenced by SLCO1B1 polymorphisms, associated with lower hepatic uptake, showing higher survival rates and toxicity in AML studies. The variant alleles of ABCB1 were related to anthracycline intracellular accumulation, increasing complete remission, survival and toxicity. Similar findings have been suggested with ABCC1 and ABCG2 polymorphisms. Polymorphisms of SLC29A1, responsible for cytarabine uptake, demonstrated significant associations with survival and response in Asian populations. Promising results were observed with SLC and ABC combinations regarding anthracycline toxicities. Knowledge of the role of transporter pharmacogenetics could explain the differences observed in drug disposition in the blast. Further studies including novel targeted therapies should be performed to determine the influence of genetic variability to individualize chemotherapy schemes. Full article
(This article belongs to the Special Issue The Role of SLC and ABC Transporters in Anti-cancer Drug Delivery)
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