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Article ; Online: New mechanisms of multidrug resistance: an introduction to the

Gottesman, Michael M / Robey, Robert W / Ambudkar, Suresh V

Cancer drug resistance (Alhambra, Calif.)

2023 Volume 6, Issue 3, Page(s) 590–595

Abstract: Cancer Drug ... ...

Abstract	Cancer Drug Resistance
Language	English
Publishing date	2023-08-17
Publishing country	United States
Document type	Editorial
ISSN	2578-532X
ISSN (online)	2578-532X
DOI	10.20517/cdr.2023.86
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Article ; Online: Progress in characterizing ABC multidrug transporters in zebrafish.

Thomas, Joanna R / Frye, William J E / Robey, Robert W / Gottesman, Michael M

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy

2023 Volume 72, Page(s) 101035

Abstract: Zebrafish have proved to be invaluable for modeling complex physiological processes shared by all vertebrate animals. Resistance of cancers and other diseases to drug treatment can occur owing to expression of the ATP-dependent multidrug transporters ... ...

Abstract	Zebrafish have proved to be invaluable for modeling complex physiological processes shared by all vertebrate animals. Resistance of cancers and other diseases to drug treatment can occur owing to expression of the ATP-dependent multidrug transporters ABCB1, ABCG2, and ABCC1, either because of expression of these transporters by the target cells to reduce intracellular concentrations of cytotoxic drugs at barrier sites such as the blood-brain barrier (BBB) to limit penetration of drugs into privileged compartments, or by affecting the absorption, distribution, and excretion of drugs administered orally, through the skin, or directly into the bloodstream. We describe the drug specificity, cellular localization, and function of zebrafish orthologs of multidrug resistance ABC transporters with the goal of developing zebrafish models to explore the physiological and pathophysiological functions of these transporters. Finally, we provide context demonstrating the utility of zebrafish in studying cancer drug resistance. Our ultimate goal is to improve treatment of cancer and other diseases which are affected by ABC multidrug resistance transporters.
MeSH term(s)	Animals ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Zebrafish/genetics ; Zebrafish/metabolism ; Membrane Transport Proteins ; Drug Resistance, Multiple/genetics ; Antineoplastic Agents/pharmacology ; Neoplasms/drug therapy ; Neoplasms/genetics
Chemical Substances	ATP-Binding Cassette Transporters ; Membrane Transport Proteins ; Antineoplastic Agents
Language	English
Publishing date	2023-12-17
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	1474513-6
ISSN	1532-2084 ; 1368-7646
ISSN (online)	1532-2084
ISSN	1368-7646
DOI	10.1016/j.drup.2023.101035
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Zs.A 5099: Show issues

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Article: Identification of NanoLuciferase Substrates Transported by Human ABCB1 and ABCG2 and their Zebrafish Homologs at the Blood-Brain Barrier.

Inglut, Collin T / Quinlan, John A / Robey, Robert W / Thomas, Joanna R / Walker, Joel R / Zhou, Wenhui / Huang, Huang-Chiao / Gottesman, Michael M

bioRxiv : the preprint server for biology

2023

Abstract: ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier (BBB) impede delivery of therapeutic agents to the brain, including agents to treat neurodegenerative diseases and primary and metastatic brain cancers. Two transporters, P- ... ...

Abstract	ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier (BBB) impede delivery of therapeutic agents to the brain, including agents to treat neurodegenerative diseases and primary and metastatic brain cancers. Two transporters, P-glycoprotein (P-gp, ABCB1) and ABCG2, are highly expressed at the BBB and are responsible for the efflux of numerous clinically useful chemotherapeutic agents, including irinotecan, paclitaxel, and doxorubicin. Based on a previous mouse model, we have generated transgenic zebrafish in which expression of NanoLuciferase (NanoLuc) is controlled by the promoter of glial fibrillary acidic protein, leading to expression in zebrafish glia. To identify agents that disrupt the BBB, including inhibitors of ABCB1 and ABCG2, we identified NanoLuc substrates that are also transported by P-gp, ABCG2, and their zebrafish homologs. These substrates will elevate the amount of bioluminescent light produced in the transgenic zebrafish with BBB disruption. We transfected HEK293 cells with NanoLuc and either human ABCB1, ABCG2, or their zebrafish homologs Abcb4 or Abcg2a, respectively, and expressed at the zebrafish BBB. We evaluated the luminescence of ten NanoLuc substrates, then screened the eight brightest to determine which are most efficiently effluxed by the ABC transporters. We identified one substrate efficiently pumped out by ABCB1, two by Abcb4, six by ABCG2, and four by Abcg2a. These data will aid in the development of a transgenic zebrafish model of the BBB to identify novel BBB disruptors and should prove useful in the development of other animal models that use NanoLuc as a reporter.
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.20.563277
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Article: Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier.

Thomas, Joanna R / Frye, William J E / Robey, Robert W / Warner, Andrew C / Butcher, Donna / Matta, Jennifer L / Morgan, Tamara C / Edmondson, Elijah F / Salazar, Paula B / Ambudkar, Suresh V / Gottesman, Michael M

bioRxiv : the preprint server for biology

2024

Abstract: Background: A principal protective component of the mammalian blood-brain barrier (BBB) is the high expression of the multidrug efflux transporters P-glycoprotein (P-gp, encoded by : Methods: To determine substrates of the transporters, we stably ... ...

Abstract	Background: A principal protective component of the mammalian blood-brain barrier (BBB) is the high expression of the multidrug efflux transporters P-glycoprotein (P-gp, encoded by Methods: To determine substrates of the transporters, we stably expressed each in HEK-293 cells and performed cytotoxicity and fluorescent efflux assays with known ABCG2 substrates. To assess the expression of transporter homologs, we used a combination of RNAscope Results: We found Abcg2a had the greatest substrate overlap with ABCG2, and Abcg2d appeared to be the least functionally similar. We identified Conclusions: These results demonstrate the conserved function of zebrafish Abcg2a and suggest that zebrafish may be an appropriate model organism for the studying the role of ABCG2 at the BBB.
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.18.539313
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Article ; Online: Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier.

Fluids and barriers of the CNS

2024 Volume 21, Issue 1, Page(s) 27

Abstract: Background: A principal protective component of the mammalian blood-brain barrier (BBB) is the high expression of the multidrug efflux transporters P-glycoprotein (P-gp, encoded by ABCB1) and ABCG2 (encoded by ABCG2) on the lumenal surface of ... ...

Abstract	Background: A principal protective component of the mammalian blood-brain barrier (BBB) is the high expression of the multidrug efflux transporters P-glycoprotein (P-gp, encoded by ABCB1) and ABCG2 (encoded by ABCG2) on the lumenal surface of endothelial cells. The zebrafish P-gp homolog Abcb4 is expressed at the BBB and phenocopies human P-gp. Comparatively little is known about the four zebrafish homologs of the human ABCG2 gene: abcg2a, abcg2b, abcg2c, and abcg2d. Here we report the functional characterization and brain tissue distribution of zebrafish ABCG2 homologs. Methods: To determine substrates of the transporters, we stably expressed each in HEK-293 cells and performed cytotoxicity and fluorescent efflux assays with known ABCG2 substrates. To assess the expression of transporter homologs, we used a combination of RNAscope in situ hybridization probes and immunohistochemistry to stain paraffin-embedded sections of adult and larval zebrafish. Results: We found Abcg2a had the greatest substrate overlap with ABCG2, and Abcg2d appeared to be the least functionally similar. We identified abcg2a as the only homolog expressed at the adult and larval zebrafish BBB, based on its localization to claudin-5 positive brain vasculature. Conclusions: These results demonstrate the conserved function of zebrafish Abcg2a and suggest that zebrafish may be an appropriate model organism for studying the role of ABCG2 at the BBB.
MeSH term(s)	Adult ; Animals ; Humans ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Blood-Brain Barrier/metabolism ; Endothelial Cells/metabolism ; HEK293 Cells ; Mammals/metabolism ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Zebrafish/metabolism
Chemical Substances	ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins
Language	English
Publishing date	2024-03-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2595406-4
ISSN	2045-8118 ; 2045-8118
ISSN (online)	2045-8118
ISSN	2045-8118
DOI	10.1186/s12987-024-00529-5
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Article ; Online: The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species.

González Dalmasy, José M / Fitzsimmons, Christina M / Frye, William J E / Perciaccante, Andrew J / Jewell, Connor P / Jenkins, Lisa M / Batista, Pedro J / Robey, Robert W / Gottesman, Michael M

Chemico-biological interactions

2024 Volume 394, Page(s) 110989

Abstract: Although few resistance mechanisms for histone deacetylase inhibitors (HDACis) have been described, we recently demonstrated that TMT1A (formerly METTL7A) and TMT1B (formerly METTL7B) can mediate resistance to HDACis with a thiol as the zinc-binding ... ...

Abstract	Although few resistance mechanisms for histone deacetylase inhibitors (HDACis) have been described, we recently demonstrated that TMT1A (formerly METTL7A) and TMT1B (formerly METTL7B) can mediate resistance to HDACis with a thiol as the zinc-binding group by methylating and inactivating the drug. TMT1A and TMT1B are poorly characterized, and their normal physiological role has yet to be determined. As animal model systems are often used to determine the physiological function of proteins, we investigated whether the ability of these methyltransferases to methylate thiol-based HDACis is conserved across different species. We found that TMT1A was conserved across rats, mice, chickens, and zebrafish, displaying 85.7%, 84.8%, 60.7%, and 51.0% amino acid sequence identity, respectively, with human TMT1A. Because TMT1B was not found in the chicken or zebrafish, we focused our studies on the TMT1A homologs. HEK-293 cells were transfected to express mouse, rat, chicken, or zebrafish homologs of TMT1A and all conferred resistance to the thiol-based HDACIs NCH-51, KD-5170, and romidepsin compared to empty vector-transfected cells. Additionally, all homologs blunted the downstream effects of HDACi treatment such as increased p21 expression, increased acetylated histone H3, and cell cycle arrest. Increased levels of dimethylated romidepsin were also found in the culture medium of cells transfected to express any of the TMT1A homologs after a 24 h incubation with romidepsin compared to empty-vector transfected cells. Our results indicate that the ability of TMT1A to methylate molecules is conserved across species. Animal models may therefore be useful in elucidating the role of these enzymes in humans.
MeSH term(s)	Animals ; Humans ; Mice ; Methyltransferases/metabolism ; Methyltransferases/genetics ; HEK293 Cells ; Zebrafish/metabolism ; Rats ; Chickens ; Histone Deacetylase Inhibitors/pharmacology ; Amino Acid Sequence ; Sulfhydryl Compounds/metabolism ; Depsipeptides/pharmacology ; Methylation ; Species Specificity ; Conserved Sequence
Chemical Substances	Methyltransferases (EC 2.1.1.-) ; Histone Deacetylase Inhibitors ; Sulfhydryl Compounds ; romidepsin (CX3T89XQBK) ; Depsipeptides
Language	English
Publishing date	2024-04-03
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	218799-1
ISSN	1872-7786 ; 0009-2797
ISSN (online)	1872-7786
ISSN	0009-2797
DOI	10.1016/j.cbi.2024.110989
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Zs.A 686: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Multidrug transporters: recent insights from cryo-electron microscopy-derived atomic structures and animal models.

Lusvarghi, Sabrina / Robey, Robert W / Gottesman, Michael M / Ambudkar, Suresh V

F1000Research

2020 Volume 9

Abstract: P-glycoprotein, ABCG2, and MRP1 are members of the ATP-binding cassette (ABC) transporter superfamily that utilize energy from ATP-binding and hydrolysis to efflux a broad range of chemically dissimilar substrates including anticancer drugs. As a ... ...

Abstract	P-glycoprotein, ABCG2, and MRP1 are members of the ATP-binding cassette (ABC) transporter superfamily that utilize energy from ATP-binding and hydrolysis to efflux a broad range of chemically dissimilar substrates including anticancer drugs. As a consequence, they play an important role in the pharmacokinetics and bioavailability of many drugs; in particular, their role in multidrug resistance in cancer cells as well as at the blood-brain barrier has been the subject of studies for decades. However, the atomic structures of these transporters in the presence of substrates or modulators and at different stages of the ATP-hydrolysis cycle have only recently been resolved by using cryo-electron microscopy. In addition, new animal models have shed new light on our understanding of the role of these transporters at the blood-brain barrier. This new information should open doors for the design of novel chemotherapeutics and treatments to bypass recognition by ABC drug pumps to overcome clinical drug resistance. In this review, we discuss the most recent advances in our understanding of ligand interactions and mechanistic aspects of drug transport based on atomic structures of these transporters as well as the development of new
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters/chemistry ; Animals ; Cryoelectron Microscopy ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Models, Animal ; Multidrug Resistance-Associated Proteins
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters ; Multidrug Resistance-Associated Proteins ; multidrug resistance-associated protein 1 (Y49M64GZ4Q)
Language	English
Publishing date	2020-01-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	2699932-8
ISSN	2046-1402 ; 2046-1402
ISSN (online)	2046-1402
ISSN	2046-1402
DOI	10.12688/f1000research.21295.1
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Article ; Online: The multidrug resistance transporter P-glycoprotein confers resistance to ferroptosis inducers.

Frye, William J E / Huff, Lyn M / González Dalmasy, José M / Salazar, Paula / Carter, Rachel M / Gensler, Ryan T / Esposito, Dominic / Robey, Robert W / Ambudkar, Suresh V / Gottesman, Michael M

Cancer drug resistance (Alhambra, Calif.)

2023 Volume 6, Issue 6, Page(s) 468–480

Abstract: Aim: ...

Abstract	Aim:
Language	English
Publishing date	2023-07-27
Publishing country	United States
Document type	Journal Article
ISSN	2578-532X
ISSN (online)	2578-532X
DOI	10.20517/cdr.2023.29
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Article ; Online: Carrier-Free, Amorphous Verteporfin Nanodrug for Enhanced Photodynamic Cancer Therapy and Brain Drug Delivery.

Quinlan, John A / Inglut, Collin T / Srivastava, Payal / Rahman, Idrisa / Stabile, Jillian / Gaitan, Brandon / Arnau Del Valle, Carla / Baumiller, Kaylin / Gaur, Anandita / Chiou, Wen-An / Karim, Baktiar / Connolly, Nina / Robey, Robert W / Woodworth, Graeme F / Gottesman, Michael M / Huang, Huang-Chiao

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

2024 , Page(s) e2302872

Abstract: Glioblastoma (GBM) is hard to treat due to cellular invasion into functioning brain tissues, limited drug delivery, and evolved treatment resistance. Recurrence is nearly universal even after surgery, chemotherapy, and radiation. Photodynamic therapy ( ... ...

Abstract	Glioblastoma (GBM) is hard to treat due to cellular invasion into functioning brain tissues, limited drug delivery, and evolved treatment resistance. Recurrence is nearly universal even after surgery, chemotherapy, and radiation. Photodynamic therapy (PDT) involves photosensitizer administration followed by light activation to generate reactive oxygen species at tumor sites, thereby killing cells or inducing biological changes. PDT can ablate unresectable GBM and sensitize tumors to chemotherapy. Verteporfin (VP) is a promising photosensitizer that relies on liposomal carriers for clinical use. While lipids increase VP's solubility, they also reduce intracellular photosensitizer accumulation. Here, a pure-drug nanoformulation of VP, termed "NanoVP", eliminating the need for lipids, excipients, or stabilizers is reported. NanoVP has a tunable size (65-150 nm) and 1500-fold higher photosensitizer loading capacity than liposomal VP. NanoVP shows a 2-fold increase in photosensitizer uptake and superior PDT efficacy in GBM cells compared to liposomal VP. In mouse models, NanoVP-PDT improved tumor control and extended animal survival, outperforming liposomal VP and 5-aminolevulinic acid (5-ALA). Moreover, low-dose NanoVP-PDT can safely open the blood-brain barrier, increasing drug accumulation in rat brains by 5.5-fold compared to 5-ALA. NanoVP is a new photosensitizer formulation that has the potential to facilitate PDT for the treatment of GBM.
Language	English
Publishing date	2024-03-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2808093-2
ISSN	2198-3844 ; 2198-3844
ISSN (online)	2198-3844
ISSN	2198-3844
DOI	10.1002/advs.202302872
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Article ; Online: Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model.

Lim, Sanghee / Kwak, Minhye / Kang, Jeonghan / Cesaire, Melissa / Tang, Kayen / Robey, Robert W / Frye, William J E / Karim, Baktiar / Butcher, Donna / Lizak, Martin J / Dalmage, Mahalia / Foster, Brandon / Nuechterlein, Nicholas / Eberhart, Charles / Cimino, Patrick J / Gottesman, Michael M / Jackson, Sadhana

Acta neuropathologica communications

2024 Volume 12, Issue 1, Page(s) 56

Abstract: In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently ... ...

Abstract	In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently impair aortic endothelial adhesion and increase rodent glioma model survival in combination with cytotoxic therapy. Yet additional research is required to understand ibrutinib's effect on BTB function. In this study, we detail baseline BTK expression in glioma cells and its surrounding vasculature, then measure endothelial junctional expression/function changes with varied ibrutinib doses in vitro. Rat glioma cells and rodent glioma models were treated with ibrutinib alone (1-10 µM and 25 mg/kg) and in combination with doxil (10-100 µM and 3 mg/kg) to assess additive effects on viability, drug concentrations, tumor volume, endothelial junctional expression and survival. We found that ibrutinib, in a dose-dependent manner, decreased brain endothelial cell-cell adhesion over 24 h, without affecting endothelial cell viability (p < 0.005). Expression of tight junction gene and protein expression was decreased maximally 4 h after administration, along with inhibition of efflux transporter, ABCB1, activity. We demonstrated an additive effect of ibrutinib with doxil on rat glioma cells, as seen by a significant reduction in cell viability (p < 0.001) and increased CNS doxil concentration in the brain (56 ng/mL doxil alone vs. 74.6 ng/mL combination, p < 0.05). Finally, Ibrutinib, combined with doxil, prolonged median survival in rodent glioma models (27 vs. 16 days, p < 0.0001) with brain imaging showing a - 53% versus - 75% volume change with doxil alone versus combination therapy (p < 0.05). These findings indicate ibrutinib's ability to increase brain endothelial permeability via junctional disruption and efflux inhibition, to increase BTB drug entry and prolong rodent glioma model survival. Our results motivate the need to identify other BTB modifiers, all with the intent of improving survival and reducing systemic toxicities.
MeSH term(s)	Rats ; Animals ; Rodentia ; Glioma/pathology ; Antineoplastic Agents/therapeutic use ; Blood-Brain Barrier/pathology ; Adenine/analogs & derivatives ; Doxorubicin/analogs & derivatives ; Piperidines ; Polyethylene Glycols
Chemical Substances	liposomal doxorubicin ; ibrutinib (1X70OSD4VX) ; Antineoplastic Agents ; Adenine (JAC85A2161) ; Doxorubicin (80168379AG) ; Piperidines ; Polyethylene Glycols (3WJQ0SDW1A)
Language	English
Publishing date	2024-04-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-024-01763-6
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