In Vitro Screening of Three Commercial Cannabis-Based Products on ATP-Binding Cassette and Solute-Carrier Transporter Function

Chemotherapeutics tumor resistance is a principal reason for treatment failure, and clinical and experimental data indicate that multidrug transporters such as ATP-binding cassette (ABC) B1 and ABCG2 play a leading role by preventing cytotoxic intracellular drug concentrations. Functional efflux inhibition of existing chemotherapeutics by these pumps continues to present a promising approach for treatment. A contributing factor to the failure of existing inhibitors in clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We have identified selective efflux inhibitors by profiling multiple ABC transporters against a library of small molecules to find molecular probes to further explore such interactions. In our primary screening protocol using JC-1 as a dual-pump fluorescent reporter substrate, we identified a piperazine-substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure-activity relationship (SAR)–driven chemistry effort, we describe compound 1 (CID44640177), an efflux inhibitor with selectivity toward ABCG2 over ABCB1. Compound 1 is also shown to potentiate the activity of mitoxantrone in vitro as well as preliminarily in vivo in an ABCG2-overexpressing tumor model. At least two analogues significantly reduce tumor size in combination with the chemotherapeutic topotecan. To our knowledge, low nanomolar chemoreversal activity coupled with direct evidence of efflux inhibition for ABCG2 is unprecedented.

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Endocrine Disruptors Differentially Target ATP-Binding Cassette Transporters in the Blood-Testis Barrier and Affect Leydig Cell Testosterone Secretion In Vitro

Toxicological Sciences ◽

10.1093/toxsci/kft198 ◽

2013 ◽

Vol 136 (2) ◽

pp. 382-391 ◽

Cited By ~ 52

Author(s):

Anita C. A. Dankers ◽

Maarke J. E. Roelofs ◽

Aldert H. Piersma ◽

Fred C. G. J. Sweep ◽

Frans G. M. Russel ◽

...

Keyword(s):

Endocrine Disruptors ◽

Leydig Cell ◽

Atp Binding ◽

Testosterone Secretion ◽

Atp Binding Cassette Transporters ◽

Blood Testis Barrier ◽

Atp Binding Cassette

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Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.634948 ◽

2021 ◽

Vol 13 ◽

Author(s):

Dongmei Wu ◽

Yang Hu ◽

Min Song ◽

Gongbo Li

Keyword(s):

Amyloid Beta ◽

Critical Role ◽

Liver X Receptor ◽

Dynamics Simulation ◽

Atp Binding ◽

Atp Binding Cassette Transporter ◽

Liver X Receptor Α ◽

Aβ Clearance ◽

Atp Binding Cassette

Abnormal amyloid beta (Aβ) clearance is a distinctive pathological mechanism for Alzheimer’s disease (AD). ATP-binding cassette transporter A1 (ABCA1), which mediates the lipidation of apolipoprotein E, plays a critical role in Aβ clearance. As an environmental factor for AD, dichlorodiphenyltrichloroethane (DDT) can decrease ATP-binding cassette transporter A1 (ABCA1) expression and disrupt Aβ clearance. Liver X receptor α (LXRα) is an autoregulatory transcription factor for ABCA1 and a target of some environmental pollutants, such as organophosphate pesticides. In this study, we aimed to investigate whether DDT could affect Aβ clearance by targeting LXRα. The DDT-pretreated H4 human neuroglioma cells and immortalized astrocytes were incubated with exogenous Aβ to evaluate Aβ consumption. Meanwhile, cytotoxicity and LXRα expression were determined in the DDT-treated cells. Subsequently, the antagonism of DDT on LXRα agonist T0901317 was determined in vitro. The interaction between DDT and LXRα was predicted by molecular docking and molecular dynamics simulation technology. We observed that DDT could inhibit Aβ clearance and decrease the levels of LXRα mRNA and LXRα protein. Moreover, DDT is supposed to strongly bind to LXRα and exert antagonistic effects on LXRα. In conclusion, this study firstly presented that DDT could inhibit LXRα expression, which would contribute to Aβ clearance decline in vitro. It provides an experimental basis to search for potential therapeutic targets of AD.

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NtcA-Dependent Expression of the devBCAOperon, Encoding a Heterocyst-Specific ATP-Binding Cassette Transporter in Anabaena spp

Journal of Bacteriology ◽

10.1128/jb.183.12.3795-3799.2001 ◽

2001 ◽

Vol 183 (12) ◽

pp. 3795-3799 ◽

Cited By ~ 35

Author(s):

Gabriele Fiedler ◽

Alicia M. Muro-Pastor ◽

Enrique Flores ◽

Iris Maldener

Keyword(s):

Nitrogen Deficiency ◽

Transcriptional Regulator ◽

Atp Binding ◽

Translation Start Site ◽

Atp Binding Cassette Transporter ◽

Translation Start ◽

Transcriptional Start Point ◽

Pcc 7120 ◽

Atp Binding Cassette

ABSTRACT The devBCA operon, encoding subunits of an ATP-binding cassette exporter, is essential for differentiation of N2-fixing heterocysts in Anabaena spp. Nitrogen deficiency-dependent transcription of the operon and the use of its transcriptional start point, located 762 (Anabaena variabilis strain ATCC 29413-FD) or 704 (Anabaena sp. strain PCC 7120) bp upstream of the translation start site, were found to require the global nitrogen transcriptional regulator NtcA. Furthermore, NtcA was shown to bind in vitro to the promoter ofdevBCA.

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Gene Expression Profiling of Transporters in the Solute Carrier and ATP-Binding Cassette Superfamilies in Human Eye Substructures

Molecular Pharmaceutics ◽

10.1021/mp300429e ◽

2013 ◽

Vol 10 (2) ◽

pp. 650-663 ◽

Cited By ~ 31

Author(s):

Amber Dahlin ◽

Ethan Geier ◽

Sophie L. Stocker ◽

Cheryl D. Cropp ◽

Elena Grigorenko ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Atp Binding ◽

Human Eye ◽

Solute Carrier ◽

Atp Binding Cassette

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Role of ATP-Binding-Cassette Transporter Genes in High-Frequency Acquisition of Resistance to Azole Antifungals in Candida glabrata

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.4.1174-1183.2001 ◽

2001 ◽

Vol 45 (4) ◽

pp. 1174-1183 ◽

Cited By ~ 169

Author(s):

Dominique Sanglard ◽

Francoise Ischer ◽

Jacques Bille

Keyword(s):

Abc Transporter ◽

High Frequency ◽

Candida Glabrata ◽

Antifungal Agents ◽

Clinical Isolates ◽

Azole Resistance ◽

Atp Binding ◽

Transporter Gene ◽

Atp Binding Cassette

ABSTRACT Candida glabrata has been often isolated from AIDS patients with oropharyngeal candidiasis treated with azole antifungal agents, especially fluconazole. We recently showed that the ATP-binding-cassette (ABC) transporter gene CgCDR1 was upregulated in C. glabrata clinical isolates resistant to azole antifungal agents (D. Sanglard, F. Ischer, D. Calabrese, P. A. Majcherczyk, and J. Bille, Antimicrob. Agents Chemother. 43:2753–2765, 1999). Deletion of CgCDR1 in C. glabrata rendered the null mutant hypersusceptible to azole derivatives and showed the importance of this gene in mediating azole resistance. We observed that wild-type C. glabrata exposed to fluconazole in a medium containing the drug at 50 μg/ml developed resistance to this agent and other azoles at a surprisingly high frequency (2 × 10−4 to 4 × 10−4). We show here that this high-frequency azole resistance (HFAR) acquired in vitro was due, at least in part, to the upregulation ofCgCDR1. The CgCDR1 deletion mutant DSY1041 could still develop HFAR but in a medium containing fluconazole at 5 μg/ml. In the HFAR strain derived from DSY1041, a distinct ABC transporter gene similar to CgCDR1, calledCgCDR2, was upregulated. This gene was slightly expressed in clinical isolates but was upregulated in strains with the HFAR phenotype. Deletion of both CgCDR1 and CgCDR2suppressed the development of HFAR in a medium containing fluconazole at 5 μg/ml, showing that both genes are important mediators of resistance to azole derivatives in C. glabrata. We also show here that the HFAR phenomenon was linked to the loss of mitochondria in C. glabrata. Mitochondrial loss could be obtained by treatment with ethidium bromide and resulted in acquisition of resistance to azole derivatives without previous exposure to these agents. Azole resistance obtained in vitro by HFAR or by agents stimulating mitochondrial loss was at least linked to the upregulation of both CgCDR1 and CgCDR2.

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Role of ATP-Binding Cassette and Solute Carrier Transporters in Erlotinib CNS Penetration and Intracellular Accumulation

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-10-1934 ◽

2010 ◽

Vol 17 (1) ◽

pp. 89-99 ◽

Cited By ~ 73

Author(s):

Mohamed A. Elmeliegy ◽

Angel M. Carcaboso ◽

Michael Tagen ◽

Feng Bai ◽

Clinton F. Stewart

Keyword(s):

Atp Binding ◽

Intracellular Accumulation ◽

Solute Carrier Transporters ◽

Solute Carrier ◽

Cns Penetration ◽

Atp Binding Cassette

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Evidence for a Role of the Adenosine 5′-Triphosphate-Binding Cassette Transporter A1 in the Externalization of Annexin I from Pituitary Folliculo-Stellate Cells

Endocrinology ◽

10.1210/en.2002-220650 ◽

2003 ◽

Vol 144 (3) ◽

pp. 1062-1073 ◽

Cited By ~ 46

Author(s):

Lee P. Chapman ◽

Matthew J. Epton ◽

Julia C. Buckingham ◽

John F. Morris ◽

Helen C. Christian

Keyword(s):

Abc Transporters ◽

Anterior Pituitary ◽

Signal Sequence ◽

Atp Binding ◽

Annexin I ◽

Adenocarcinoma Cells ◽

Inhibitory Feedback ◽

Immunofluorescence Labeling ◽

Atp Binding Cassette

Annexin 1 (ANXA1) has a well-demonstrated role in early delayed inhibitory feedback of glucocorticoids in the pituitary. ANXA1 is located in folliculo-stellate (FS) cells, and glucocorticoids act on these cells to externalize and stimulate the synthesis of ANXA1. However, ANXA1 lacks a signal sequence so the mechanism by which ANXA1 is externalized from FS cells was unknown and has been investigated. The ATP-binding cassette (ABC) transporters are a large group of transporters with varied roles that include the externalization of proteins. Glucocorticoid-induced externalization of ANXA1 from an FS cell line (TtT/GF) and rat anterior pituitary was blocked by glyburide, which inhibits ABC transporters. Glyburide also blocked the glucocorticoid inhibition of forskolin-stimulated ACTH release from pituitary tissue in vitro. RT-PCR revealed mRNA and Western blotting demonstrated protein for the ATP binding cassette A1 (ABCA1) transporter in mouse FS, TtT/GF, and A549 lung adenocarcinoma cells from which glucocorticoids also induce externalization of ANXA1. In TtT/GF cells, immunofluorescence labeling revealed a near total colocalization of cell surface ANXA1 and ABCA1. We conclude that ANXA1, which mediates the early delayed feedback of glucocorticoids in the anterior pituitary, is externalized from FS cells by an ABC transporter and that the ABCA1 transporter is a likely candidate.

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