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1.
Mol Pharmacol ; 101(6): 381-389, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35383108

RESUMEN

The organic anion transporting polypeptide family member (OATP) 1B3 is a hepatic uptake transporter that has a broad substrate recognition and plays a significant role in regulating elimination of endogenous biomolecules or xenobiotics. OATP1B3 works in tandem with OATP1B1, with which it shares approximately 80% sequence homology and a high degree of substrate overlap. Despite some substrates being recognized solely by OATP1B3, its ability to compensate for loss of OATP1B1-mediated elimination and recognition by regulatory agencies, little is known about OATP1B3 regulatory factors and how they are involved with drug-drug interaction. It was recently discovered that OATP1B1 function is mediated by the activity of a particular tyrosine kinase that is sensitive to a variety of tyrosine kinase inhibitors (TKIs). This study reports that OATP1B3 is similarly regulated, as at least 50% of its activity is reduced by 20 US Food and Drug Administration -approved TKIs. Nilotinib was assessed as the most potent OATP1B3 inhibitor among the investigated TKIs, which can occur at clinically relevant concentrations and acted predominantly through noncompetitive inhibition without impacting membrane expression. Finally, OATP1B3 function was determined to be sensitive to the knockdown of the Lck/Yes novel tyrosine kinase that is sensitive to nilotinib and has been previously implicated in mediating OATP1B1 activity. Collectively, our findings identify tyrosine kinase activity as a major regulator of OATP1B3 function which is sensitive to kinase inhibition. Given that OATP1B1 is similarly regulated, simultaneous disruption of these transporters can have drastic effects on systemic drug concentrations, which would promote adverse events. SIGNIFICANCE STATEMENT: The organic anion transporting polypeptide family member (OATP) 1B3 is a facilitator of hepatic drug elimination, although much is unknown of how OATP1B3 activity is mediated, or how such regulators contribute to drug-drug interactions. This study reports that OATP1B3 activity is dependent on the Lck/Yes novel tyrosine kinase, which is sensitive to numerous tyrosine kinase inhibitors. These findings provide insight into the occurrence of many clinical drug-drug interactions, and a rationale for future study of tyrosine kinases regulating drug disposition.


Asunto(s)
Transportadores de Anión Orgánico , Proteínas Tirosina Quinasas , Interacciones Farmacológicas , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo
2.
Mol Pharmacol ; 100(4): 348-355, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34330821

RESUMEN

Cisplatin is a platinum-based drug, which remains among the most efficacious anticancer treatment options. Unfortunately, use of cisplatin is hindered by dose-limiting toxicities, including irreversible hearing loss, which can grossly affect patient quality of life. Cisplatin-induced ototoxicity is the result of cochlear hair cell damage through a mechanism that is poorly understood. However, cisplatin cytotoxicity is reliant on intracellular accumulation, a process that is largely dependent on the presence of particular membrane transporters. This review will provide an update on our current understanding of the various transporters known to be involved in the disposition and cytotoxicity of platinum drugs or their metabolites, as well as their role in mediating cisplatin-induced hearing loss. We also provide a summary of the successes and opportunities in therapeutically targeting membrane transporters to alleviate platinum-induced hearing loss. Moreover, we describe how this approach could be used to reduce the severity or onset of other adverse events associated with exposure to various forms of platinum drugs, without diminishing antitumor efficacy. SIGNIFICANCE STATEMENT: Cisplatin-induced hearing loss is a dose-limiting and irreversible adverse event with no current preventative or curative treatment measures. Pharmacological targeting of membrane transporters that regulate platinum uptake into cochlear hair cells, if conducted appropriately, may alleviate this devastating side effect and could be applied to alleviate other platinum-induced toxicities.


Asunto(s)
Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Sistemas de Liberación de Medicamentos/tendencias , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Pérdida Auditiva/prevención & control , Humanos , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportador 2 de Cátion Orgánico/antagonistas & inhibidores , Transportador 2 de Cátion Orgánico/metabolismo
3.
Proc Natl Acad Sci U S A ; 112(16): 5231-6, 2015 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-25848011

RESUMEN

Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.


Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Puntos de Control del Ciclo Celular , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Lesión Renal Aguda/patología , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Cisplatino , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Células HEK293 , Células HeLa , Humanos , Túbulos Renales/efectos de los fármacos , Túbulos Renales/enzimología , Túbulos Renales/patología , Ratones , Proteínas de Transporte de Catión Orgánico/deficiencia , Proteínas de Transporte de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Purinas/farmacología , Purinas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico
4.
Proc Natl Acad Sci U S A ; 110(27): 11199-204, 2013 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-23776246

RESUMEN

Oxaliplatin is an integral component of colorectal cancer therapy, but its clinical use is associated with a dose-limiting peripheral neurotoxicity. We found that the organic cation transporter 2 (OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate. Cellular uptake of oxaliplatin was increased by 16- to 35-fold in cells overexpressing mouse Oct2 or human OCT2, and this process was associated with increased DNA platination and oxaliplatin-induced cytotoxicity. Furthermore, genetic or pharmacologic knockout of Oct2 protected mice from hypersensitivity to cold or mechanical-induced allodynia, which are established tests to assess acute oxaliplatin-induced neurotoxicity. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity.


Asunto(s)
Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/metabolismo , Proteínas de Transporte de Catión Orgánico/fisiología , Compuestos Organoplatinos/toxicidad , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Femenino , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Síndromes de Neurotoxicidad/genética , Factor 1 de Transcripción de Unión a Octámeros/deficiencia , Factor 1 de Transcripción de Unión a Octámeros/genética , Factor 1 de Transcripción de Unión a Octámeros/fisiología , Proteínas de Transporte de Catión Orgánico/deficiencia , Proteínas de Transporte de Catión Orgánico/genética , Transportador 2 de Cátion Orgánico , Compuestos Organoplatinos/farmacocinética , Oxaliplatino
5.
Drug Metab Dispos ; 42(4): 611-22, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24378324

RESUMEN

Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics in multiple tissues. Many of these transporters are highly expressed in the gastrointestinal tract, liver, and kidney and are considered to be of particular importance in governing drug absorption, elimination, and cellular sensitivity of specific organs to a wide variety of oncology drugs. Although the majority of studies on the interaction of oncology drugs with SLC have been restricted to the use of exploratory in vitro model systems, emerging evidence suggests that several SLCs, including OCT2 and OATP1B1, contribute to clinically important phenotypes associated with those agents. Recent literature has indicated that modulation of SLC activity may result in drug-drug interactions, and genetic polymorphisms in SLC genes have been described that can affect the handling of substrates. Alteration of SLC function by either of these mechanisms has been demonstrated to contribute to interindividual variability in the pharmacokinetics and toxicity associated with several oncology drugs. In this report, we provide an update on this rapidly emerging field.


Asunto(s)
Antineoplásicos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Humanos , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Distribución Tisular
6.
Pharmaceutics ; 16(4)2024 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-38675109

RESUMEN

A large percentage (~60%) of prescription drugs and new molecular entities are designed for oral delivery, which requires passage through a semi-impervious membrane bilayer in the gastrointestinal wall. Passage through this bilayer can be dependent on membrane transporters that regulate the absorption of nutrients or endogenous substrates. Several investigations have provided links between nutrient, endogenous substrate, or drug absorption and the activity of certain membrane transporters. This knowledge has been key in the development of new therapeutics that can alleviate various symptoms of select diseases, such as cholestasis and diabetes. Despite this progress, recent studies revealed potential clinical dangers of unintended altered nutrient or endogenous substrate disposition due to the drug-mediated disruption of intestinal transport activity. This review outlines reports of glucose, folate, thiamine, lactate, and bile acid (re)absorption changes and consequent adverse events as examples. Finally, the need to comprehensively expand research on intestinal transporter-mediated drug interactions to avoid the unwanted disruption of homeostasis and diminish therapeutic adverse events is highlighted.

7.
Drug Resist Updat ; 15(1-2): 5-20, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22459901

RESUMEN

Members of the solute carrier family of transporters are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. Several of these solute carriers are known to be expressed in cancer cells or cancer cell lines, and decreased cellular uptake of drugs potentially contributes to the development of resistance. As result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. In this review article, we provide an update of this rapidly emerging field, with specific emphasis on the direct contribution of solute carriers to anticancer drug uptake in tumors, the role of these carriers in regulation of anticancer drug disposition, and recent advances in attempts to evaluate these proteins as therapeutic targets.


Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Transporte de Membrana/metabolismo , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacocinética , Humanos , Proteínas de Transporte de Membrana/genética , Ratones , Neoplasias/genética , Neoplasias/metabolismo , Ratas
8.
Breast Cancer Res ; 14(1): R2, 2012 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-22225778

RESUMEN

INTRODUCTION: The taxanes paclitaxel and docetaxel are widely used in the treatment of breast, ovarian, and other cancers. Although their cytotoxicity has been attributed to cell-cycle arrest through stabilization of microtubules, the mechanisms by which tumor cells die remains unclear. Paclitaxel has been shown to induce soluble tumor necrosis factor alpha (sTNF-α) production in macrophages, but the involvement of TNF production in taxane cytotoxicity or resistance in tumor cells has not been established. Our study aimed to correlate alterations in the TNF pathway with taxane cytotoxicity and the acquisition of taxane resistance. METHODS: MCF-7 cells or isogenic drug-resistant variants (developed by selection for surviving cells in increasing concentrations of paclitaxel or docetaxel) were assessed for sTNF-α production in the absence or presence of taxanes by enzyme-linked immunosorbent assay (ELISA) and for sensitivity to docetaxel or sTNF-α by using a clonogenic assay (in the absence or presence of TNFR1 or TNFR2 neutralizing antibodies). Nuclear factor (NF)-κB activity was also measured with ELISA, whereas gene-expression changes associated with docetaxel resistance in MCF-7 and A2780 cells were determined with microarray analysis and quantitative reverse transcription polymerase chain reaction (RTqPCR). RESULTS: MCF-7 and A2780 cells increased production of sTNF-α in the presence of taxanes, whereas docetaxel-resistant variants of MCF-7 produced high levels of sTNF-α, although only within a particular drug-concentration threshold (between 3 and 45 nM). Increased production of sTNF-α was NF-κB dependent and correlated with decreased sensitivity to sTNF-α, decreased levels of TNFR1, and increased survival through TNFR2 and NF-κB activation. The NF-κB inhibitor SN-50 reestablished sensitivity to docetaxel in docetaxel-resistant MCF-7 cells. Gene-expression analysis of wild-type and docetaxel-resistant MCF-7, MDA-MB-231, and A2780 cells identified changes in the expression of TNF-α-related genes consistent with reduced TNF-induced cytotoxicity and activation of NF-κB survival pathways. CONCLUSIONS: We report for the first time that taxanes can promote dose-dependent sTNF-α production in tumor cells at clinically relevant concentrations, which can contribute to their cytotoxicity. Defects in the TNF cytotoxicity pathway or activation of TNF-dependent NF-κB survival genes may, in contrast, contribute to taxane resistance in tumor cells. These findings may be of strong clinical significance.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Paclitaxel/farmacología , Transducción de Señal , Taxoides/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Neoplasias de la Mama , Supervivencia Celular/efectos de los fármacos , Cicloheximida/farmacología , Docetaxel , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Células MCF-7 , FN-kappa B/metabolismo , Neoplasias Ováricas , Inhibidores de la Síntesis de la Proteína/farmacología , Proteolisis , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Activación Transcripcional/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética
9.
BMC Cancer ; 12: 381, 2012 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-22938713

RESUMEN

BACKGROUND: Since proteins involved in chemotherapy drug pharmacokinetics and pharmacodynamics have a strong impact on the uptake, metabolism, and efflux of such drugs, they likely play critical roles in resistance to chemotherapy drugs in cancer patients. METHODS: To investigate this hypothesis, we conducted a whole genome microarray study to identify difference in the expression of genes between isogenic doxorubicin-sensitive and doxorubicin-resistant MCF-7 breast tumour cells. We then assessed the degree of over-representation of doxorubicin pharmacokinetic and pharmacodynamic genes in the dataset of doxorubicin resistance genes. RESULTS: Of 27,958 Entrez genes on the array, 7.4 per cent or 2,063 genes were differentially expressed by ≥ 2-fold between wildtype and doxorubicin-resistant cells. The false discovery rate was set at 0.01 and the minimum p value for significance for any gene within the "hit list" was 0.01. Seventeen and 43 per cent of doxorubicin pharmacokinetic genes were over-represented in the hit list, depending upon whether the gene name was identical or within the same gene family, respectively. The most over-represented genes were within the 1C and 1B families of aldo-keto reductases (AKRs), which convert doxorubicin to doxorubicinol. Other genes convert doxorubicin to other metabolites or affect the influx, efflux, or cytotoxicity of the drug. In further support of the role of AKRs in doxorubicin resistance, we observed that, in comparison to doxorubicin, doxorubincol exhibited dramatically reduced cytotoxicity, reduced DNA-binding activity, and strong localization to extra nuclear lysosomes. Pharmacologic inhibition of the above AKRs in doxorubicin-resistant cells increased cellular doxorubicin levels, restored doxorubicin cytotoxicity and re-established doxorubicin localization to the nucleus. The properties of doxorubicinol were unaffected. CONCLUSIONS: These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledge bases to identify highly relevant genes associated with doxorubicin resistance. The induction of one or more of these genes was found to be correlated with changes in the drug's properties, while inhibiting one specific class of these genes (the AKRs) increased cellular doxorubicin content and restored drug DNA binding, cytotoxicity, and subcellular localization.


Asunto(s)
Aldehído Reductasa/genética , Aldehído Reductasa/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , 20-Hidroxiesteroide Deshidrogenasas/biosíntesis , 20-Hidroxiesteroide Deshidrogenasas/genética , 20-Hidroxiesteroide Deshidrogenasas/metabolismo , 3-Hidroxiesteroide Deshidrogenasas/biosíntesis , 3-Hidroxiesteroide Deshidrogenasas/genética , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Aldehído Reductasa/biosíntesis , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas , Aldo-Ceto Reductasas , Neoplasias de la Mama/metabolismo , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Ácidos Cólicos/farmacología , Ciclosporina/farmacología , ADN de Neoplasias/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica , Humanos , Hidroxiprostaglandina Deshidrogenasas/biosíntesis , Hidroxiprostaglandina Deshidrogenasas/genética , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Células MCF-7 , Análisis de Secuencia por Matrices de Oligonucleótidos
10.
Clin Pharmacol Ther ; 112(3): 461-484, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35390174

RESUMEN

Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post-translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation-mediated changes in transporter function on drug disposition and response.


Asunto(s)
Proteínas Portadoras , Proteínas de Transporte de Membrana , Transporte Biológico , Proteínas Portadoras/metabolismo , Regulación de la Expresión Génica , Humanos , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Preparaciones Farmacéuticas , Receptores Citoplasmáticos y Nucleares/genética
11.
Clin Cancer Res ; 27(15): 4301-4310, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-33664059

RESUMEN

PURPOSE: OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug-drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKI). EXPERIMENTAL DESIGN: OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI were measured in vivo. Tyrosine phosphorylation of OATP1B1 was determined by LC/MS-MS-based proteomics and transport function was measured following exposure to siRNAs targeting 779 different kinases. RESULTS: Twenty-nine of 46 FDA-approved TKIs studied significantly inhibit OATP1B1 function. Inhibition of OATP1B1 by TKIs, such as nilotinib, is predominantly noncompetitive, can increase systemic concentrations of rosuvastatin in vivo, and is associated with reduced phosphorylation of OATP1B1 at tyrosine residue 645. Using genetic screens and functional validation studies, the Src kinase LYN was identified as a potential regulator of OATP1B1 activity that is highly sensitive to inhibition by various TKIs at clinically relevant concentrations. CONCLUSIONS: A novel kinase-dependent posttranslational mechanism of OATP1B1 activation was identified and interference with this process by TKIs can influence the elimination of a broad range of xenobiotic substrates.


Asunto(s)
Células HEK293/metabolismo , Hepatocitos/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/fisiología , Proteínas Tirosina Quinasas/fisiología , Animales , Humanos , Ratones , Fosforilación
12.
J Clin Invest ; 130(9): 4601-4606, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32484793

RESUMEN

Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventive strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.


Asunto(s)
Neuroglía/metabolismo , Neuronas/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Transportador 2 de Cátion Orgánico/metabolismo , Oxaliplatino , Animales , Femenino , Masculino , Ratones , Ratones Noqueados , Neuroglía/patología , Neuronas/patología , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/patología , Transportador 2 de Cátion Orgánico/genética , Oxaliplatino/efectos adversos , Oxaliplatino/farmacocinética , Oxaliplatino/farmacología , Ratas
13.
Clin Pharmacol Ther ; 104(5): 799-802, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30028006

RESUMEN

Toxicity is among the greatest concerns during clinical use of drugs, and it has been well documented that transporter proteins facilitate such events by regulating drug accumulation. However, an important question is whether strategies could be adopted to diminish such toxicities. Although the field is currently in its infancy, some examples exist demonstrating how mechanistic understanding of the role of transporters in drug disposition can aid in alleviating transporter-mediated toxic effects.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Moduladores del Transporte de Membrana/farmacología , Proteínas de Transporte de Membrana/efectos de los fármacos , Preparaciones Farmacéuticas/metabolismo , Animales , Transporte Biológico , Interacciones Farmacológicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Genotipo , Humanos , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Variantes Farmacogenómicas , Fenotipo , Medición de Riesgo
14.
Clin Pharmacol Ther ; 104(5): 900-915, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29756222

RESUMEN

Drug transporters are critically important for the absorption, distribution, metabolism, and excretion (ADME) of many drugs and endogenous compounds. Therefore, disruption of these pathways by inhibition, induction, genetic polymorphisms, or disease can have profound effects on overall physiology, drug pharmacokinetics, drug efficacy, and toxicity. This white paper provides a review of changes in transporter function associated with acute and chronic disease states, describes regulatory pathways affecting transporter expression, and identifies opportunities to advance the field.


Asunto(s)
Enfermedad Aguda , Enfermedad Crónica/tratamiento farmacológico , Moduladores del Transporte de Membrana/farmacología , Proteínas de Transporte de Membrana/efectos de los fármacos , Proteínas de Transporte de Membrana/metabolismo , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Animales , Interacciones Farmacológicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Humanos , Moduladores del Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Modelos Biológicos , Medición de Riesgo
15.
J Clin Invest ; 128(2): 816-825, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29337310

RESUMEN

Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion-transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.


Asunto(s)
Hiperalgesia/inducido químicamente , Transportador 1 de Anión Orgánico Específico del Hígado/deficiencia , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Paclitaxel/toxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Pirimidinas/farmacología , Animales , Antineoplásicos/toxicidad , Biomarcadores/metabolismo , Línea Celular Tumoral , Genotipo , Células HEK293 , Humanos , Hiperalgesia/prevención & control , Concentración 50 Inhibidora , Células MCF-7 , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Ratones Transgénicos , Transportadores de Anión Orgánico/genética , Enfermedades del Sistema Nervioso Periférico/prevención & control , Fenotipo
16.
Nat Commun ; 7: 10880, 2016 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-26979622

RESUMEN

Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive 'transporter-phosphoproteome' with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation.


Asunto(s)
Proteínas de Transporte de Catión Orgánico/efectos de los fármacos , Fosfotirosina/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-yes/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Ganglios Espinales/efectos de los fármacos , Células HEK293 , Células HeLa , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado , Ratones , Modelos Moleculares , Transportadores de Anión Orgánico/efectos de los fármacos , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Transportador 1 de Catión Orgánico/efectos de los fármacos , Transportador 1 de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico , Compuestos Organoplatinos/farmacología , Oxaliplatino , Fosfotirosina/metabolismo , Proteínas Tirosina Quinasas/efectos de los fármacos , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-yes/metabolismo
17.
Pharmacogenomics ; 16(4): 323-32, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25823781

RESUMEN

AIM: Assuming that genetic variants of the SLC22A2 and SLC31A1 transporter affect patients' susceptibility to cisplatin-induced ototoxicity, we compared the distribution of 11 SLC22A2 variants and the SLC31A1 variant rs10981694 between patients with and without cisplatin-induced ototoxicity. PATIENTS & METHODS: Genotyping was performed in 64 pediatric patients and significant findings were re-evaluated in 66 adults. RESULTS: The SLC22A2 polymorphism rs316019 (c.808G>T; Ser270Ala) was significantly associated with protection from cisplatin-induced ototoxicity in the pediatric (p = 0.022) and the adult cohort (p = 0.048; both: Fisher's exact test). This result was confirmed by multiple logistic regression analysis accounting for age which was identified as a relevant factor for ototoxicity as well (rs316019: OR [G/T vs G/G] = 0.12, p = 0.009; age: OR [per year]: 0.84, p = 0.02). CONCLUSION: These results identified rs316019 as potential pharmacogenomic marker for cisplatin-induced ototoxicity and point to a critical role of SLC22A2 for cisplatin transport in humans and its contribution to the organ specific side effects of this drug. Original submitted 17 September 2014; Revision submitted 19 December 2014.


Asunto(s)
Proteínas de Transporte de Catión/genética , Cisplatino/efectos adversos , Neoplasias/tratamiento farmacológico , Proteínas de Transporte de Catión Orgánico/genética , Adolescente , Adulto , Niño , Preescolar , Cisplatino/administración & dosificación , Transportador de Cobre 1 , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Masculino , Neoplasias/genética , Neoplasias/patología , Transportador 2 de Cátion Orgánico , Polimorfismo de Nucleótido Simple
18.
Clin Cancer Res ; 20(15): 4026-35, 2014 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-24916697

RESUMEN

PURPOSE: Tubular secretion of cisplatin is abolished in mice deficient for the organic cation transporters Oct1 and Oct2 (Oct1/2(-/-)mice), and these animals are protected from severe cisplatin-induced kidney damage. Since tubular necrosis is not completely absent in Oct1/2(-/-)mice, we hypothesized that alternate pathways are involved in the observed injury. EXPERIMENTAL DESIGN: Studies were done in wild-type, Oct1/2(-/-), or p53-deficient animals, all on an FVB background, receiving cisplatin intraperitoneally at 15 mg/kg. Cisplatin metabolites were analyzed using mass spectrometry, and gene expression was assessed using Affymetrix microarrays and RT-PCR arrays. RESULTS: KEGG pathway analyses on kidneys from mice exposed to cisplatin revealed that the most significantly altered genes were associated with the p53 signaling network, including Cdnk1a and Mdm2, in both wild-type (P = 2.40 × 10(-11)) and Oct1/2(-/-)mice (P = 1.92 × 10(-8)). This was confirmed by demonstrating that homozygosity for a p53-null allele partially reduced renal tubular damage, whereas loss of p53 in Oct1/2(-/-)mice (p53(-/-)/Oct1/2(-/-)) completely abolished nephrotoxicity. We found that pifithrin-α, an inhibitor of p53-dependent transcriptional activation, inhibits Oct2 and can mimic the lack of nephrotoxicity observed in p53(-/-)/Oct1/2(-/-)mice. CONCLUSIONS: These findings indicate that (i) the p53 pathway plays a crucial role in the kidney in response to cisplatin treatment and (ii) clinical exploration of OCT2 inhibitors may not lead to complete nephroprotection unless the p53 pathway is simultaneously antagonized.


Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Factor 1 de Transcripción de Unión a Octámeros/fisiología , Proteínas de Transporte de Catión Orgánico/fisiología , Proteína p53 Supresora de Tumor/fisiología , Animales , Antineoplásicos/metabolismo , Benzotiazoles/farmacología , Biomarcadores/metabolismo , Cisplatino/metabolismo , Femenino , Perfilación de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Enfermedades Renales/patología , Masculino , Ratones , Ratones Noqueados , Factor 1 de Transcripción de Unión a Octámeros/antagonistas & inhibidores , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Transportador 2 de Cátion Orgánico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tolueno/análogos & derivados , Tolueno/farmacología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores
19.
Drug Metab Pharmacokinet ; 28(1): 19-27, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-22986709

RESUMEN

Several solute carriers and ATP-binding cassette transporters have been implicated in the influx or efflux of platinum-based chemotherapeutic agents such as cisplatin, carboplatin, and oxaliplatin. Given that many of these proteins are highly polymorphic, the genetic status of these proteins could be an important contributor to the extensive interindividual pharmacokinetic variability associated with the clinical use of these agents. In this review article, we provide an updated overview of the various transporters that have shown promise in animal models or patient populations in facilitating the movement of platinum-based agents across cell membranes, and how their function is associated with drug disposition or pharmacodynamic effects.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Transporte de Membrana/genética , Compuestos de Platino/farmacología , Compuestos de Platino/farmacocinética , Animales , Proteínas de Transporte de Catión/genética , Transportador de Cobre 1 , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas de Transporte de Catión Orgánico/genética , Polimorfismo de Nucleótido Simple
20.
Mol Cancer Ther ; 12(8): 1537-44, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23757163

RESUMEN

Expression of the human organic anion transporting polypeptides OATP1B1 and OATP1B3 has been previously believed to be restricted to hepatocytes. Here we show that the gene encoding OATP1B3, but not OATP1B1, is abundantly expressed in multiple human solid tumors that include hepatocellular, lung, and ovarian carcinomas. Surprisingly, OATP1B3 gene expression in a panel of 60 human tumor cell lines was linked with sensitivity to multiple cytotoxic agents, including the platinum anticancer drugs cisplatin, carboplatin, and oxaliplatin. In addition, overexpression of OATP1B3 in mammalian cells increased cellular accumulation of platinum agents and decreased cell survival. In mice with a targeted disruption of the ortholog transporter Oatp1b2, the liver-to-plasma ratio of cisplatin was significantly reduced compared with wild-type mice, without concurrent changes in expression profiles of other transporter genes. Our findings indicate an unexpected role for tumoral and host OATP1B-type carriers in the toxicity and disposition of platinum anticancer drugs, and may provide a foundation for understanding the extensive interindividual pharmacodynamic variability seen with these drugs in patients.


Asunto(s)
Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Transportadores de Anión Orgánico/metabolismo , Platino (Metal)/metabolismo , Platino (Metal)/farmacología , Animales , Antineoplásicos/farmacocinética , Transporte Biológico , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Expresión Génica , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Ratones , Neoplasias/genética , Neoplasias/metabolismo , Transportadores de Anión Orgánico/deficiencia , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico Sodio-Independiente/genética , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Platino (Metal)/farmacocinética , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos
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