RESUMEN
AIMS: Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo. METHODS: Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo. RESULTS: Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2. CONCLUSIONS: These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Lansoprazol , Lisosomas , Ratones Desnudos , Inhibidores de la Bomba de Protones , Ensayos Antitumor por Modelo de Xenoinjerto , Lansoprazol/farmacología , Animales , Humanos , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones , Inhibidores de la Bomba de Protones/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Simulación del Acoplamiento Molecular , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Proteínas de NeoplasiasRESUMEN
Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25-2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38⯵M. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia.
Asunto(s)
Linezolid , Trombocitopenia , Linezolid/efectos adversos , Linezolid/farmacocinética , Humanos , Trombocitopenia/inducido químicamente , Trombocitopenia/metabolismo , Células HEK293 , Animales , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Ratas , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/farmacología , Lansoprazol/farmacología , Transporte Biológico , Ratas Sprague-Dawley , Factores de Riesgo , Adulto , Transportadores de Anión Orgánico Sodio-Independiente/metabolismoRESUMEN
The study investigates the potential of lansoprazole, a proton pump inhibitor, to interfere with fungal respiration and enhance the antifungal activity of amphotericin B against multidrug-resistant Candida auris. The authors administered lansoprazole at concentrations significantly higher than typical therapeutic doses, which demonstrated promising results but also raised concerns about potential toxicity. We suggest incorporating a control group, monitoring toxicity indicators, performing pathological examinations, and conducting cellular assays to improve the study's rigor and reliability. We also highlight the need for further research into the mechanisms of lansoprazole's antifungal activity, its long-term effects on amphotericin B resistance, and potential drug-drug interactions with amphotericin B. Addressing these concerns is crucial for the clinical translation of lansoprazole as an adjuvant to amphotericin B.
Asunto(s)
Anfotericina B , Antifúngicos , Candida auris , Farmacorresistencia Fúngica Múltiple , Sinergismo Farmacológico , Lansoprazol , Pruebas de Sensibilidad Microbiana , Lansoprazol/farmacología , Anfotericina B/farmacología , Antifúngicos/farmacología , Humanos , Candida auris/efectos de los fármacos , Candida auris/genética , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Inhibidores de la Bomba de Protones/farmacologíaRESUMEN
Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB's activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc1). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (â¼98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome bc1 inhibitor for combating drug-resistant C. auris infections.