A Micellar Formulation of Quercetin Prevents Cisplatin Nephrotoxicity

Casanova, Alfredo G.; Prieto, Marta; Colino, Clara I.; Gutiérrez-Millán, Carmen; Ruszkowska-Ciastek, Barbara; Paz, Esther de; Martín, Ángel; Morales, Ana Isabel; López‐Hernández, Francisco J.

doi:10.3390/ijms22020729

Cited by 26 publications

(20 citation statements)

References 65 publications

(43 reference statements)

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“…A few more examples of flavonoids, such as artocarpanone, artocarpin, cycloartocarpin, and cyanomaclurin, extracted from Artocarpus heterophyllus heartwoods have a synergistic effect with cisplatin on non-small lung and breast cancers [145]. Recent studies have shown that quercetin prevented cisplatin nephrotoxicity by ameliorating tubular damage [146]. Isoquercetin and rutin, flavonoids from Morus alba, have been shown to enhance the therapeutic efficacy of cisplatin significantly compared to a single dose of cisplatin alone in treating gastric cancer [147].…”

Section: Combination With Flavonoidsmentioning

confidence: 99%

Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy

Dasari

Njiki

Mbemi

et al. 2022

IJMS

142

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Cisplatin and other platinum-based drugs, such as carboplatin, ormaplatin, and oxaliplatin, have been widely used to treat a multitude of human cancers. However, a considerable proportion of patients often relapse due to drug resistance and/or toxicity to multiple organs including the liver, kidneys, gastrointestinal tract, and the cardiovascular, hematologic, and nervous systems. In this study, we sought to provide a comprehensive review of the current state of the science highlighting the use of cisplatin in cancer therapy, with a special emphasis on its molecular mechanisms of action, and treatment modalities including the combination therapy with natural products. Hence, we searched the literature using various scientific databases., such as MEDLINE, PubMed, Google Scholar, and relevant sources, to collect and review relevant publications on cisplatin, natural products, combination therapy, uses in cancer treatment, modes of action, and therapeutic strategies. Our search results revealed that new strategic approaches for cancer treatment, including the combination therapy of cisplatin and natural products, have been evaluated with some degree of success. Scientific evidence from both in vitro and in vivo studies demonstrates that many medicinal plants contain bioactive compounds that are promising candidates for the treatment of human diseases, and therefore represent an excellent source for drug discovery. In preclinical studies, it has been demonstrated that natural products not only enhance the therapeutic activity of cisplatin but also attenuate its chemotherapy-induced toxicity. Many experimental studies have also reported that natural products exert their therapeutic action by triggering apoptosis through modulation of mitogen-activated protein kinase (MAPK) and p53 signal transduction pathways and enhancement of cisplatin chemosensitivity. Furthermore, natural products protect against cisplatin-induced organ toxicity by modulating several gene transcription factors and inducing cell death through apoptosis and/or necrosis. In addition, formulations of cisplatin with polymeric, lipid, inorganic, and carbon-based nano-drug delivery systems have been found to delay drug release, prolong half-life, and reduce systemic toxicity while other formulations, such as nanocapsules, nanogels, and hydrogels, have been reported to enhance cell penetration, target cancer cells, and inhibit tumor progression.

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Section: Combination With Flavonoidsmentioning

confidence: 99%

Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy

Dasari

Njiki

Mbemi

et al. 2022

IJMS

142

View full text Add to dashboard Cite

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“…Based on those results, quercetin 3-O-glucuronide could be responsible, at least in part, for the nephroprotective effect of quercetin against cisplatin damage observed in vivo [3,15]. Furthermore, the protective effect of the metabolite could explain our in vivo results regarding to the absence of protection of oral P-quercetin, when the same formulation has previously been shown to be effective intraperitoneally [16]. The differences observed between the administration of P-quercetin by the intraperitoneal and oral vias cannot be explained by its absorption, since it seems to be very similar for both routes.…”

Section: Discussionmentioning

confidence: 55%

“…In our in vivo model, renal function was heavily damaged by cisplatin. However, this effect was not ameliorated by oral P-quercetin, as was the case with intraperitoneal administration of the formulation in our previous experiments [16]. Rats in the cisplatin (CP) group experienced an acute kidney injury (AKI), as they showed a progressive increase in their plasma creatinine (Crpl) and urea levels compared to those of the controls (Figure 1a).…”

Section: Nephroprotection Study With Oral P-quercetinmentioning

confidence: 78%

“…In order to improve its bioavailability, we have developed a micellar formulation (P-quercetin), which increases quercetin solubility approximately 10 times. Our results showed that this formulation, administered i.p., increased the plasma concentration of quercetin compared to the dose-equivalent administration of the unformulated flavonoid, and maintained the nephroprotective capacity when it was coadministered with cisplatin [16].…”

Section: Introductionmentioning

confidence: 96%

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Protective Effect of Quercetin 3-O-Glucuronide against Cisplatin Cytotoxicity in Renal Tubular Cells

et al. 2022

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Quercetin, a flavonoid with promising therapeutic potential, has been shown to protect from cisplatin nephrotoxicity in rats following intraperitoneal injection, but its low bioavailability curtails its prospective clinical utility in oral therapy. We recently developed a micellar formulation (P-quercetin) with enhanced solubility and bioavailability, and identical nephroprotective properties. As a first aim, we herein evaluated the oral treatment with P-quercetin in rats, which displayed no nephroprotection. In order to unravel this discrepancy, quercetin and its main metabolites were measured by HPLC in the blood and urine after intraperitoneal and oral administrations. Whilst quercetin was absorbed similarly, the profile of its metabolites was different, which led us to hypothesize that nephroprotection might be exerted in vivo by a metabolic derivate. Consequently, we then aimed to evaluate the cytoprotective capacity of quercetin and its main metabolites (quercetin 3-O-glucoside, rutin, tamarixetin, isorhamnetin and quercetin 3-O-glucuronide) against cisplatin toxicity, in HK-2 and NRK-52E tubular cell lines. Cells were incubated for 6 h with quercetin, its metabolites or vehicle (pretreatment), and subsequently 18 h in cotreatment with 10–300 μM cisplatin. Immediately after treatment, cell cultures were subject to the MTT technique as an index of cytotoxicity and photographed under light microscopy for phenotypic assessment. Quercetin afforded no direct cytoprotection and quercetin-3-O-glucuronide was the only metabolite partially preventing the effect of cisplatin in cultured tubule cells. Our results identify a metabolic derivative of quercetin contributing to its nephroprotection and prompt to further explore exogenous quercetin-3-O-glucuronide in the prophylaxis of tubular nephrotoxicity.

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“…The possibility of clarifying these aspects would allow us to establish strategies such as the encapsulation of an active metabolite to favor its accumulation in the kidney. In our laboratory, it has been shown that the encapsulation of quercetin with Pluronic F127 enhances the biopharmaceutical properties, increases the bioavailability of the flavonoid, and maintains the renoprotective properties against quercetin aglycone [74]. Similarly, the encapsulation of the active metabolite would facilitate its access to the tubular cell, its renal metabolism, and its accumulation.…”

Section: Aspects To Be Elucidated and Limitations Of Current Studiesmentioning

confidence: 99%

Transit and Metabolic Pathways of Quercetin in Tubular Cells: Involvement of Its Antioxidant Properties in the Kidney

2021

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Quercetin is a flavonoid with antioxidant, antiviral, antimicrobial, and anti-inflammatory properties. Therefore, it has been postulated as a molecule with great therapeutic potential. The renoprotective capacity of quercetin against various toxins that produce oxidative stress, in both in vivo and in vitro models, has been shown. However, it is not clear whether quercetin itself or any of its metabolites are responsible for the protective effects on the kidney. Although the pharmacokinetics of quercetin have been widely studied and the complexity of its transit throughout the body is well known, the metabolic processes that occur in the kidney are less known. Because of that, the objective of this review was to delve into the molecular and cellular events triggered by quercetin and/or its metabolites in the tubular cells, which could explain some of the protective properties of this flavonoid against oxidative stress produced by toxin administration. Thus, the following are analyzed: (1) the transit of quercetin to the kidney; (2) the uptake mechanisms of quercetin and its metabolites from plasma to the tubular cells; (3) the metabolic processes triggered in those cells, which affect the accumulation of metabolites in the intracellular space; and (4) the efflux mechanisms of these compounds and their subsequent elimination through urine. Finally, it is discussed whether those processes that are mediated in the tubular cells and that give rise to different metabolites are related to the antioxidant and renoprotective properties observed after the administration of quercetin.

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A Micellar Formulation of Quercetin Prevents Cisplatin Nephrotoxicity

Cited by 26 publications

References 65 publications

Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy

Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy

Protective Effect of Quercetin 3-O-Glucuronide against Cisplatin Cytotoxicity in Renal Tubular Cells

Transit and Metabolic Pathways of Quercetin in Tubular Cells: Involvement of Its Antioxidant Properties in the Kidney

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