Moving toward a new horizon for the aldose reductase inhibitor epalrestat to treat drug-resistant cancer

Bailly, Christian

doi:10.1016/j.ejphar.2022.175191

Cited by 18 publications

(12 citation statements)

References 88 publications

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“…Epalrestat, as the only AR inhibitor currently approved for clinical application, is used for the treatment of diabetic neuropathy by improving cell activity, and can be more specific and stable targeted inhibition of AR, with lasting efficacy and low side effects [ 25 , 58 ]. Meantime, epalrestat has stronger brain permeability and can fully enter the central nervous system to play its role [ 22 , 23 , 59 ]. Senthilkumari et al [ 60 ] showed that epalrestat can inhibit apoptosis and appeared to be beneficial in reducing diabetes-related complications in retinal pigment epithelial cells under high-glucose conditions.…”

Section: Discussionmentioning

confidence: 99%

The Aldose Reductase Inhibitor Epalrestat Maintains Blood–Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

Zhang

Xin-min

et al. 2023

Mol Neurobiol

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Excessive activation of aldose reductase (AR) in the brain is a risk factor for aggravating cerebral ischemia injury. Epalrestat is the only AR inhibitor with proven safety and efficacy, which is used in the clinical treatment of diabetic neuropathy. However, the molecular mechanisms underlying the neuroprotection of epalrestat remain unknown in the ischemic brain. Recent studies have found that blood–brain barrier (BBB) damage was mainly caused by increased apoptosis and autophagy of brain microvascular endothelial cells (BMVECs) and decreased expression of tight junction proteins. Thus, we hypothesized that the protective effect of epalrestat is mainly related to regulating the survival of BMVECs and tight junction protein levels after cerebral ischemia. To test this hypothesis, a mouse model of cerebral ischemia was established by permanent middle cerebral artery ligation (pMCAL), and the mice were treated with epalrestat or saline as a control. Epalrestat reduced the ischemic volume, enhanced BBB function, and improved the neurobehavior after cerebral ischemia. In vitro studies revealed that epalrestat increased the expression of tight junction proteins, and reduced the levels of cleaved-caspase3 and LC3 proteins in mouse BMVECs (bEnd.3 cells) exposed to oxygen–glucose deprivation (OGD). In addition, bicalutamide (an AKT inhibitor) and rapamycin (an mTOR inhibitor) increased the epalrestat-induced reduction in apoptosis and autophagy related protein levels in bEnd.3 cells with OGD treatment. Our findings suggest that epalrestat improves BBB function, which may be accomplished by reducing AR activation, promoting tight junction proteins expression, and upregulating AKT/mTOR signaling pathway to inhibit apoptosis and autophagy in BMVECs.

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Section: Discussionmentioning

confidence: 99%

The Aldose Reductase Inhibitor Epalrestat Maintains Blood–Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

Zhang

Xin-min

et al. 2023

Mol Neurobiol

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“…The Bradford (1976) technique at 595 nm was used to determine the protein content of the samples (Özaslan et al, 2018;Sever et al, 2020a). Sodium dodecyl sulphate-polyacrylamide gel electrophoresis technique (Laemmli, 1970) was employed to ensure enzyme purity (Alım et al, 2019;Demir, 2020;Demir & Köksal, 2019, 2022. AR activity was assessed spectrophotometrically using DL-glyceraldehyde and NADPH reduction at 340 nm as described in previous studies (Demir et al, 2019a(Demir et al, , 2020bSever et al, 2021aSever et al, , 2021bTürkeş et al, 2022b).…”

Section: Enzyme Inhibition Studymentioning

confidence: 99%

“…From the acetic acid derivatives, only epalrestat (EPR) is used as an antidiabetic drug and is marketed by ONO Pharmaceutical (Shehzad et al, 2021). Furthermore, recent studies have indicated that inhibition of AR can attenuate diabetes as well as cancer and many diseases, thereby reducing disease progression, and there is much research about the development and potential use of new and more potent ARIs for the selective treatment of cancer (Bailly, 2022; M. Singh et al, 2021; Sonowal & Ramana, 2021).…”

Section: Introductionmentioning

confidence: 99%

Novel acetic acid derivatives containing quinazolin‐4(3H)‐one ring: Synthesis, in vitro, and in silico evaluation of potent aldose reductase inhibitors

Tokalı

Demir

Türkeş

et al. 2023

Drug Development Research

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Aldose reductase (AR) is a crucial enzyme of the polyol pathway through which glucose is metabolized under conditions of hyperglycemia related to diabetes. A series of novel acetic acid derivatives containing quinazolin-4(3H)-one ring (1-22) was synthesized and tested for in vitro AR inhibitory effect. All the target compounds exhibited nanomolar activity against the target enzyme, and all compounds displayed higher activity as compared to the reference drug epalrestat.Among them, Compound 19, named 2-(4-[(2-[(4-methylpiperazin-1-yl)methyl]-4oxoquinazolin-3(4H)-ylimino)methyl]phenoxy)acetic acid, displayed the strongest inhibitory effect with a K I value of 61.20 ± 10.18 nM. Additionally, these compounds were investigated for activity against L929, nontumoral fibroblast cells, and MCF-7, breast cancer cells using the MTT assay. Compounds 16 and 19 showed lower toxicity against the normal L929 cells. The synthesized compounds' (1-22) absorption, distribution, metabolism, and excretion properties were also evaluated.Molecular docking simulations were used to look into the possible binding mechanisms of these inhibitors against AR.

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“…Epalrestat is a potent inhibitor of aldose reductases used for decades in Japan for the treatment of diabetic peripheral neuropathy. Recent trials revealed that Epalrestat has revealed a major anticancer effect in an experimental model of basal-like breast cancer (Bailly 2022). It is uncertain whether vitamin B supplements change pain intensity or impairment in the short or long term in people with DPN (Khalil et al 2021).…”

Section: -Treatment Based On Pathogenetic Mechanismsmentioning

confidence: 99%

A new look for the management of Painful Peripheral Neuropathy in Diabetes

Elnahaas

2023

Medicine Updates

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Moving toward a new horizon for the aldose reductase inhibitor epalrestat to treat drug-resistant cancer

Cited by 18 publications

References 88 publications

The Aldose Reductase Inhibitor Epalrestat Maintains Blood–Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

The Aldose Reductase Inhibitor Epalrestat Maintains Blood–Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

Novel acetic acid derivatives containing quinazolin‐4(3H)‐one ring: Synthesis, in vitro, and in silico evaluation of potent aldose reductase inhibitors

A new look for the management of Painful Peripheral Neuropathy in Diabetes

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