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Article ; Online: Renal Organic Anion Transporters 1 and 3 In Vitro: Gone but Not Forgotten.

Caetano-Pinto, Pedro / Stahl, Simone H

International journal of molecular sciences

2023 Volume 24, Issue 20

Abstract: Organic anion transporters 1 and 3 (OAT1 and OAT3) play a crucial role in kidney function by regulating the secretion of multiple renally cleared small molecules and toxic metabolic by-products. Assessing the activity of these transporters is essential ... ...

Abstract	Organic anion transporters 1 and 3 (OAT1 and OAT3) play a crucial role in kidney function by regulating the secretion of multiple renally cleared small molecules and toxic metabolic by-products. Assessing the activity of these transporters is essential for drug development purposes as they can significantly impact drug disposition and safety. OAT1 and OAT3 are amongst the most abundant drug transporters expressed in human renal proximal tubules. However, their expression is lost when cells are isolated and cultured in vitro, which is a persistent issue across all human and animal renal proximal tubule cell models, including primary cells and cell lines. Although it is well known that the overall expression of drug transporters is affected in vitro, the underlying reasons for the loss of OAT1 and OAT3 are still not fully understood. Nonetheless, research into the regulatory mechanisms of these transporters has provided insights into the molecular pathways underlying their expression and activity. In this review, we explore the regulatory mechanisms that govern the expression and activity of OAT1 and OAT3 and investigate the physiological changes that proximal tubule cells undergo and that potentially result in the loss of these transporters. A better understanding of the regulation of these transporters could aid in the development of strategies, such as introducing microfluidic conditions or epigenetic modification inhibitors, to improve their expression and activity in vitro and to create more physiologically relevant models. Consequently, this will enable more accurate assessment for drug development and safety applications.
MeSH term(s)	Animals ; Humans ; Organic Anion Transporters, Sodium-Independent/genetics ; Organic Anion Transport Protein 1/genetics ; Organic Anion Transport Protein 1/metabolism ; Kidney/metabolism ; Kidney Tubules, Proximal/metabolism ; Epithelial Cells/metabolism ; Organic Anion Transporters/metabolism
Chemical Substances	Organic Anion Transporters, Sodium-Independent ; Organic Anion Transport Protein 1 ; Organic Anion Transporters
Language	English
Publishing date	2023-10-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242015419
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Article ; Online: Amplifying the impact of kidney microphysiological systems: predicting renal drug clearance using mechanistic modelling based on reconstructed drug secretion.

Caetano-Pinto, Pedro / Nordell, Pär / Nieskens, Tom / Haughan, Katie / Fenner, Katherine S / Stahl, Simone H

ALTEX

2022 Volume 40, Issue 3, Page(s) 408–424

Abstract: Accurate prediction of pharmacokinetic parameters, such as renal clearance, is fundamental to the development of effective and safe new treatments for patients. However, conventional renal models have a limited ability to predict renal drug secretion, a ... ...

Abstract	Accurate prediction of pharmacokinetic parameters, such as renal clearance, is fundamental to the development of effective and safe new treatments for patients. However, conventional renal models have a limited ability to predict renal drug secretion, a process that is dependent on transporters in the proximal tubule. Improvements in microphysiological systems (MPS) have extended our in vitro capabilities to predict pharmacokinetic parameters. In this study a kidney-MPS model was developed that successfully recreated renal drug secretion. Human proximal tubule cells grown in the kidney-MPS, resembling an in vivo phenotype, actively secreted the organic cation drug metformin and organic anion drug cidofovir, in contrast to cells cultured in conventional culture formats. Metformin and cidofovir renal secretory clearance were predicted from kidney-MPS data within 3.3- and 1.3-fold, respectively, of clinically reported values by employing a semi-mechanistic drug distribution model using kidney-MPS drug transport parameters together with in vitro to in vivo extrapolation. This approach introduces an effective application of a kidney-MPS model coupled with pharmacokinetic modelling tools to evaluate and predict renal drug clearance in humans. Kidney-MPS renal clearance predictions can potentially complement pharma-cokinetic animal studies and contribute to the reduction of pre-clinical species use during drug development.
MeSH term(s)	Animals ; Humans ; Cidofovir/pharmacology ; Microphysiological Systems ; Kidney/metabolism ; Metformin/metabolism ; Metformin/pharmacology ; Drug Elimination Routes
Chemical Substances	Cidofovir (JIL713Q00N) ; Metformin (9100L32L2N)
Language	English
Publishing date	2022-11-03
Publishing country	Germany
Document type	Journal Article
ZDB-ID	165707-0
ISSN	1868-8551 ; 1018-4562 ; 0946-7785
ISSN (online)	1868-8551
ISSN	1018-4562 ; 0946-7785
DOI	10.14573/altex.2204011
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Article ; Online: Recapitulating the Pharmacological Interactions of Cetuximab with Sunitinib and Cisplatin in Head and Neck Carcinoma Cells in vitro.

Dib, Maria / Justian, Nathanil / Scharf, Christian / Busch, Chia-Jung / Burchardt, Martin / Caetano-Pinto, Pedro

Pharmacology

2022 , Page(s) 1–11

Abstract: Introduction: Cisplatin is extensively used in the treatment of head and neck carcinomas. Cetuximab combination therapy is employed in recurrent and metastatic settings. Sunitinib showed positive results in the treatment of head and neck carcinomas, ... ...

Abstract	Introduction: Cisplatin is extensively used in the treatment of head and neck carcinomas. Cetuximab combination therapy is employed in recurrent and metastatic settings. Sunitinib showed positive results in the treatment of head and neck carcinomas, both as monotherapy or in combination with cetuximab. Nonetheless, the mechanism governing these pharmacological interactions is largely unresolved. This study investigates the impact of cetuximab on the cytotoxicity of cisplatin and sunitinib using cells representative of head and neck carcinoma and the oral epithelium. Methods: The uptake and efflux activities of cells were determined using the prototypical fluorescent substrates 4-[4-[dimethylamino]styryl)-1-methyl pyridinium iodide, Hoechst 33342, and calcein-AM in the presence or absence of specific inhibitors in cells pretreated with cetuximab. The expression of key uptake and efflux drug transporters was analyzed using qPCR and immunofluorescence. Cisplatin and sunitinib cytotoxicities after cetuximab pretreatment were evaluated using the PrestoBlue viability assay. Results: Both tumor and nontumor cells showed significant active drug transport activity. Cetuximab substantially deregulated the expression of key transporters involved in drug resistance in head and neck cancer cells. Transporter expression in the nontumor cell was unaffected. Upon cetuximab pretreatment, the half maximal effective toxic concentration of cisplatin was reduced by 0.75-fold and sunitinib by 0.82-fold in cancer cells. Nontumor cells were not sensitive to cisplatin or sunitinib under the conditions tested. Conclusion: Cetuximab regulates the expression and activity of key membrane drug transporters in head and neck cancer cells, involved in drug resistance. The deregulation of the transport mechanism behind cisplatin and sunitinib uptake reverses drug resistance and enhances the cytotoxicity of both drugs.
Language	English
Publishing date	2022-10-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	206671-3
ISSN	1423-0313 ; 0031-7012
ISSN (online)	1423-0313
ISSN	0031-7012
DOI	10.1159/000527082
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Article ; Conference proceedings: Investigation of Cetuximab Pretreatment Effects on Cisplatin or Sunitinib Cytotoxicity in Head and Neck Carcinoma Cells in vitro.

Dib, Maria / Busch, Chia-Jung / Justian, Nathanil / Scharf, Christian / Burchardt, Martin / Caetano-Pinto, Pedro

Laryngo-Rhino-Otologie

2023 Volume 102, Issue S 02

Event/congress	94th Annual Meeting German Society of Oto-Rhino-Laryngology, Head and Neck Surgery e.V., Bonn, Congress Center Leipzig, 2023-05-17
Language	English
Publishing date	2023-05-01
Publisher	Georg Thieme Verlag
Publishing place	Stuttgart ; New York
Document type	Article ; Conference proceedings
ZDB-ID	96005-6
ISSN	1438-8685 ; 0935-8943 ; 0340-1588
ISSN (online)	1438-8685
ISSN	0935-8943 ; 0340-1588
DOI	10.1055/s-0043-1767251
Database	Thieme publisher's database

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Article ; Online: Perspective on the Application of Microphysiological Systems to Drug Transporter Studies.

Caetano-Pinto, Pedro / Stahl, Simone H

Drug metabolism and disposition: the biological fate of chemicals

2018 Volume 46, Issue 11, Page(s) 1647–1657

Abstract: Transmembrane flux of a drug within a tissue or organ frequently involves a complex system of transporters from multiple families that have redundant and overlapping specificities. Current in vitro systems poorly represent physiology, with reduced ... ...

Abstract	Transmembrane flux of a drug within a tissue or organ frequently involves a complex system of transporters from multiple families that have redundant and overlapping specificities. Current in vitro systems poorly represent physiology, with reduced expression and activity of drug transporter proteins; therefore, novel models that recapitulate the complexity and interplay among various transporters are needed. The development of microphysiological systems that bring simulated physiologic conditions to in vitro cell culture models has enormous potential to better reproduce the morphology and transport activity across several organ models, especially in tissues such as the liver, kidney, intestine, or the blood-brain barrier, in which drug transporters play a key role. The prospect of improving the in vitro function of organ models highly prolific in drug transporters holds the promise of implementing novel tools to study these mechanisms with far more representative biology than before. In this short review, we exemplify recent developments in the characterization of perfused microphysiological systems involving the activity of drug transporters. Furthermore, we analyze the challenges and opportunities for the implementation of such systems in the study of transporter-mediated drug disposition and the generation of clinically relevant physiology-based in silico models incorporating relevant drug transport activity.
MeSH term(s)	Animals ; Biological Transport/physiology ; Blood-Brain Barrier/metabolism ; Cell Culture Techniques ; Humans ; Kidney/metabolism ; Liver/metabolism ; Membrane Transport Proteins/metabolism ; Pharmaceutical Preparations/metabolism
Chemical Substances	Membrane Transport Proteins ; Pharmaceutical Preparations
Language	English
Publishing date	2018-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.118.082750
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Article ; Online: Identification of the Regulatory Targets of miR-3687 and miR-4417 in Prostate Cancer Cells Using a Proteomics Approach.

Venz, Simone / Junker, Heike / Ultsch, Erik / Hetke, Franziska / Krüger, Elke / Burchardt, Martin / Caetano-Pinto, Pedro / Roennau, Cindy

International journal of molecular sciences

2022 Volume 23, Issue 18

Abstract: MicroRNAs (miRNA) are ubiquitous non-coding RNAs that have a prominent role in cellular regulation. The expression of many miRNAs is often found deregulated in prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). Although their ... ...

Abstract	MicroRNAs (miRNA) are ubiquitous non-coding RNAs that have a prominent role in cellular regulation. The expression of many miRNAs is often found deregulated in prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). Although their expression can be associated with PCa and CRPC, their functions and regulatory activity in cancer development are poorly understood. In this study, we used different proteomics tools to analyze the activity of hsa-miR-3687-3p (miR-3687) and hsa-miR-4417-3p (miR-4417), two miRNAs upregulated in CRPC. PCa and CRPC cell lines were transfected with miR-3687 or miR-4417 to overexpress the miRNAs. Cell lysates were analyzed using 2D gel electrophoresis and proteins were subsequently identified using mass spectrometry (Maldi-MS/MS). A whole cell lysate, without 2D-gel separation, was analyzed by ESI-MS/MS. The expression of deregulated proteins found across both methods was further investigated using Western blotting. Gene ontology and cellular process network analysis determined that miR-3687 and miR-4417 are involved in diverse regulatory mechanisms that support the CRPC phenotype, including metabolism and inflammation. Moreover, both miRNAs are associated with extracellular vesicles, which point toward a secretory mechanism. The tumor protein D52 isoform 1 (TD52-IF1), which regulates neuroendocrine trans-differentiation, was found to be substantially deregulated in androgen-insensitive cells by both miR-3687 and miR-4417. These findings show that these miRNAs potentially support the CRPC by truncating the TD52-IF1 expression after the onset of androgen resistance.
MeSH term(s)	Androgens ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; MicroRNAs/metabolism ; Prostatic Neoplasms, Castration-Resistant/pathology ; Proteomics ; Tandem Mass Spectrometry
Chemical Substances	Androgens ; MicroRNAs
Language	English
Publishing date	2022-09-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms231810565
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Article ; Online: In Vitro Characterization of Renal Drug Transporter Activity in Kidney Cancer.

Caetano-Pinto, Pedro / Justian, Nathanil / Dib, Maria / Fischer, Jana / Somova, Maryna / Burchardt, Martin / Wolff, Ingmar

International journal of molecular sciences

2022 Volume 23, Issue 17

Abstract: The activity of drug transporters is central to the secretory function of the kidneys and a defining feature of renal proximal tubule epithelial cells (RPTECs). The expression, regulation, and function of these membrane-bound proteins is well understood ... ...

Abstract	The activity of drug transporters is central to the secretory function of the kidneys and a defining feature of renal proximal tubule epithelial cells (RPTECs). The expression, regulation, and function of these membrane-bound proteins is well understood under normal renal physiological conditions. However, the impact of drug transporters on the pathophysiology of kidney cancer is still elusive. In the present study, we employed different renal cell carcinoma (RCC) cell lines and a prototypical non-malignant RPTEC cell line to characterize the activity, expression, and potential regulatory mechanisms of relevant renal drug transporters in RCC in vitro. An analysis of the uptake and efflux activity, the expression of drug transporters, and the evaluation of cisplatin cytotoxicity under the effects of methylation or epidermal growth factor receptor (EGFR) inhibition showed that the RCC cells retained substantial drug transport activity. In RCC cells, P-glycoprotein was localized in the nucleus and its pharmacological inhibition enhanced cisplatin toxicity in non-malignant RPTECs. On the other hand, methylation inhibition enhanced cisplatin toxicity by upregulating the organic cation uptake activity in RCC cells. Differential effects of methylation and EGFR were observed in transporter expression, showing regulatory heterogeneity in these cells. Interestingly, the non-malignant RPTEC cell line that was used lacked the machinery responsible for organic cation transport, which reiterates the functional losses that renal cells undergo in vitro.
MeSH term(s)	Carcinoma, Renal Cell/metabolism ; Cations/metabolism ; Cisplatin/metabolism ; Cisplatin/pharmacology ; ErbB Receptors/metabolism ; Humans ; Kidney/metabolism ; Kidney Neoplasms/metabolism ; Kidney Tubules, Proximal/metabolism ; Membrane Transport Proteins/metabolism
Chemical Substances	Cations ; Membrane Transport Proteins ; ErbB Receptors (EC 2.7.10.1) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2022-09-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms231710177
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Article ; Online: The importance of breast cancer resistance protein to the kidneys excretory function and chemotherapeutic resistance.

Caetano-Pinto, Pedro / Jansen, Jitske / Assaraf, Yehuda G / Masereeuw, Rosalinde

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

2017 Volume 30, Page(s) 15–27

Abstract: The relevance of membrane transporters gained momentum in recent years and it is now widely recognized that transporters are key players in drug disposition and chemoresistance. As such, the kidneys harbor a variety of drug transporters and are one of ... ...

Abstract	The relevance of membrane transporters gained momentum in recent years and it is now widely recognized that transporters are key players in drug disposition and chemoresistance. As such, the kidneys harbor a variety of drug transporters and are one of the main routes for xenobiotic excretion. The breast cancer resistance protein (BCRP/ABCG2) is widely accepted as a key mediator of anticancer drug resistance and is a prominent renal drug transporter. Here, we review the role of BCRP in both processes and present a multitude of variables that can influence its activity. An increasing number of renally cleared chemotherapeutics, including tyrosine kinase inhibitors, described as BCRP substrates can modulate its activity via transcription factors and cellular signaling pathways, such as the phosphoinositide 3-kinase (PI3K) pathway. In addition to pharmacological actions, genetic variations, as well as differences between species and gender can affect BCRP function, which are also discussed. Furthermore, the role of BCRP in light of cancer treatments and the implications for novel therapeutic interventions that take into account renal function are discussed.
Language	English
Publishing date	2017-01
Publishing country	Scotland
Document type	Journal Article ; Review
ZDB-ID	1474513-6
ISSN	1532-2084 ; 1368-7646
ISSN (online)	1532-2084
ISSN	1368-7646
DOI	10.1016/j.drup.2017.01.002
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Zs.A 5099: Show issues

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Article ; Online: A simple method for the isolation and detailed characterization of primary human proximal tubule cells for renal replacement therapy.

Sánchez-Romero, Natalia / Martínez-Gimeno, Laura / Caetano-Pinto, Pedro / Saez, Berta / Sánchez-Zalabardo, José Manuel / Masereeuw, Rosalinde / Giménez, Ignacio

The International journal of artificial organs

2019 Volume 43, Issue 1, Page(s) 45–57

Abstract: The main physiological functions of renal proximal tubule cells in vivo are reabsorption of essential nutrients from the glomerular filtrate and secretion of waste products and xenobiotics into urine. Currently, there are several established cell lines ... ...

Abstract	The main physiological functions of renal proximal tubule cells in vivo are reabsorption of essential nutrients from the glomerular filtrate and secretion of waste products and xenobiotics into urine. Currently, there are several established cell lines of human origin available as in vitro models of proximal tubule. However, these cells appeared to be limited in their biological relevance, because essential characteristics of the original tissue are lost once the cells are cultured. As a consequence of these limitations, primary human proximal tubule cells constitute a suitable and a biologically more relevant in vitro model to study this specific segment of the nephron and therefore, these cells can play an important role in renal regenerative medicine applications. Here, we describe a protocol to isolate proximal tubule cells from human nephrectomies. We explain the steps performed for an in-depth characterization of the cells, including the study of markers from others segments of the nephron, with the goal to determine the purity of the culture and the stability of proteins, enzymes, and transporters along time. The human proximal tubule cells isolated and used throughout this study showed many proximal tubule characteristics, including monolayer organization, cell polarization with the expression of tight junctions and primary cilia, expression of proximal tubule-specific proteins, such as megalin and sodium/glucose cotransporter 2, among others. The cells also expressed enzymatic activity for dipeptidyl peptidase IV, as well as for gamma glutamyl transferase 1, and expressed transporter activity for organic anion transporter 1, P-glycoprotein, multidrug resistance proteins, and breast cancer resistance protein. In conclusion, characterization of our cells confirmed presence of putative proximal tubule markers and the functional expression of multiple endogenous organic ion transporters mimicking renal reabsorption and excretion. These findings can constitute a valuable tool in the development of bioartificial kidney devices.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Cell Culture Techniques/methods ; Dipeptidyl Peptidase 4/metabolism ; Humans ; Kidney Tubules, Proximal/cytology ; Neoplasm Proteins/metabolism ; Nephrectomy ; Organic Anion Transporters/metabolism ; Renal Replacement Therapy ; gamma-Glutamyltransferase/metabolism
Chemical Substances	ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins ; Organic Anion Transporters ; gamma-Glutamyltransferase (EC 2.3.2.2) ; Dipeptidyl Peptidase 4 (EC 3.4.14.5)
Language	English
Publishing date	2019-08-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	80456-3
ISSN	1724-6040 ; 0391-3988
ISSN (online)	1724-6040
ISSN	0391-3988
DOI	10.1177/0391398819866458
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Article: Therapy with 2'-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption.

Janssen, Manoe J / Nieskens, Tom T G / Steevels, Tessa A M / Caetano-Pinto, Pedro / den Braanker, Dirk / Mulder, Melissa / Ponstein, Yolanda / Jones, Shaun / Masereeuw, Rosalinde / den Besten, Cathaline / Wilmer, Martijn J

Molecular therapy. Nucleic acids

2019 Volume 18, Page(s) 298–307

Abstract: Antisense oligonucleotide therapy has been reported to be associated with renal injury. Here, the mechanism of reversible proteinuria was investigated by combining clinical, pre-clinical, and in vitro data. Urine samples were obtained from Duchenne ... ...

Abstract	Antisense oligonucleotide therapy has been reported to be associated with renal injury. Here, the mechanism of reversible proteinuria was investigated by combining clinical, pre-clinical, and in vitro data. Urine samples were obtained from Duchenne muscular dystrophy (DMD) patients treated with drisapersen, a modified 2'O-methyl phosphorothioate antisense oligonucleotide (6 mg/kg). Urine and kidney tissue samples were collected from cynomolgus monkeys (Macaca fascicularis) dosed with drisapersen (39 weeks). Cell viability and protein uptake were evaluated in vitro using human conditionally immortalized proximal tubule epithelial cells (ciPTECs). Oligonucleotide treatment in DMD patients was associated with an increase in urinary alpha-1-microglobulin (A1M), which returned to baseline following treatment interruptions. In monkeys, increased urinary A1M correlated with dose-dependent accumulation of oligonucleotide in kidney tissue without evidence of tubular damage. Furthermore, oligonucleotides accumulated in the lysosomes of ciPTECs and reduced the absorption of A1M, albumin, and receptor-associated protein, but did not affect cell viability when incubated for up to 7 days. In conclusion, phosphorothioate oligonucleotides appear to directly compete for receptor-mediated endocytosis in proximal tubules. We postulate that oligonucleotide-induced low molecular weight proteinuria in patients is therefore a transient functional change and not indicative of tubular damage.
Language	English
Publishing date	2019-09-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2019.08.025
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