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Article ; Online: Emerging Perspectives on the Antiparasitic Mebendazole as a Repurposed Drug for the Treatment of Brain Cancers

Daniela Meco / Giorgio Attinà / Stefano Mastrangelo / Pierluigi Navarra / Antonio Ruggiero

International Journal of Molecular Sciences, Vol 24, Iss 1334, p

2023 Volume 1334

Abstract: Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. ... ...

Abstract	Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. The use of drugs in ways other than their original FDA-approved indications could offer novel avenues such as bypassing the chemoresistance and recurrence seen with conventional therapy and treatment; moreover, it can offer a safe and economic strategy for combination therapy. Recent works have demonstrated the anticancer properties of the FDA-approved drug Mebendazole. This synthetic benzimidazole proved effective against a broad spectrum of intestinal Helminthiasis. Mebendazole can penetrate the blood–brain barrier and has been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasion/migration, or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. Moreover, several preclinical models and ongoing clinical trials explore the efficacy of Mebendazole in multiple cancers, including acute myeloid leukemia, brain cancer, oropharyngeal squamous cell carcinoma, breast cancer, gastrointestinal cancer, lung carcinoma, adrenocortical carcinoma, prostate cancer, and head and neck cancer. The present review summarizes central literature regarding the anticancer effects of MBZ in cancer cell lines, animal tumor models, and clinical trials to suggest possible strategies for safe and economical combinations of anticancer therapies in brain cancer. Mebendazole might be an excellent candidate for the treatment of brain tumors because of its efficacy both when used as monotherapy and in combination as an enhancement to standard chemotherapeutics and radiotherapy, due to its effectiveness on tumor angiogenesis inhibition, cell cycle arrest, apoptosis induction, and targeting of critical pathways involved in cancer such as Hedgehog signaling. Therefore, attention ...
Keywords	Mebendazole ; drug repurposing ; antitumor therapy ; brain cancer ; benzimidazole ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Remifentanil does not affect human microglial immune activation in response to pro-inflammatory cytokines

Cinzia Dello Russo / Natalia Cappoli / Elisabetta Tabolacci / Liliana Sollazzi / Pierluigi Navarra / Paola Aceto

EXCLI Journal : Experimental and Clinical Sciences, Vol 22, Pp 295-

2023 Volume 309

Abstract: Remifentanil is a potent ultra-short acting μ-opioid analgesic drug, frequently used in anaesthesia due to its favorable pharmacodynamic and pharmacokinetic profile. It may be associated with the occurrence of hyperalgesia. Preclinical studies suggest a ... ...

Abstract	Remifentanil is a potent ultra-short acting μ-opioid analgesic drug, frequently used in anaesthesia due to its favorable pharmacodynamic and pharmacokinetic profile. It may be associated with the occurrence of hyperalgesia. Preclinical studies suggest a potential role of microglia, although the molecular mechanisms have not been fully elucidated. Considering the role of microglia in brain inflammation and the relevant differences among species, the effects of remifentanil were studied on the human microglial C20 cells. The drug was tested at clinically relevant concentrations under basal and inflammatory conditions. In the C20 cells, the expression and secretion of interleukin 6, interleukin 8 and the monocyte chemotactic protein 1 were rapidly induced by a mixture of pro-inflammatory cytokines. This stimulatory effect was sustained up to 24 h. Remifentanil did not exert any toxic effect nor modify the production of these inflammatory mediators, thus suggesting the lack of direct immune modulatory actions on human microglia.
Keywords	human microglia ; remifentanil ; hyperalgesia ; interleukin-6 ; interleukin-8 ; monocyte chemotactic protein 1 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: mTOR Inhibition Is Effective against Growth, Survival and Migration, but Not against Microglia Activation in Preclinical Glioma Models

Lucia Lisi / Michela Pizzoferrato / Gabriella Maria Pia Ciotti / Maria Martire / Pierluigi Navarra

International Journal of Molecular Sciences, Vol 24, Iss 9834, p

2023 Volume 9834

Abstract: Initially introduced in therapy as immunosuppressants, the selective inhibitors of mTORC1 have been approved for the treatment of solid tumors. Novel non-selective inhibitors of mTOR are currently under preclinical and clinical developments in oncology, ... ...

Abstract	Initially introduced in therapy as immunosuppressants, the selective inhibitors of mTORC1 have been approved for the treatment of solid tumors. Novel non-selective inhibitors of mTOR are currently under preclinical and clinical developments in oncology, attempting to overcome some limitations associated with selective inhibitors, such as the development of tumor resistance. Looking at the possible clinical exploitation in the treatment of glioblastoma multiforme, in this study we used the human glioblastoma cell lines U87MG, T98G and microglia (CHME-5) to compare the effects of a non-selective mTOR inhibitor, sapanisertib, with those of rapamycin in a large array of experimental paradigms, including (i) the expression of factors involved in the mTOR signaling cascade, (ii) cell viability and mortality, (iii) cell migration and autophagy, and (iv) the profile of activation in tumor-associated microglia. We could distinguish between effects of the two compounds that were overlapping or similar, although with differences in potency and or/time-course, and effects that were diverging or even opposite. Among the latter, especially relevant is the difference in the profile of microglia activation, with rapamycin being an overall inhibitor of microglia activation, whereas sapanisertib was found to induce an M2-profile, which is usually associated with poor clinical outcomes.
Keywords	mTOR ; rapamycin ; sapanisertib ; glioblastoma ; microglia ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: P2X7 receptors exert a permissive effect on the activation of presynaptic AMPA receptors in rat trigeminal caudal nucleus glutamatergic nerve terminals

Diego Currò / Pierluigi Navarra / Irene Samengo / Maria Martire

The Journal of Headache and Pain, Vol 21, Iss 1, Pp 1-

2020 Volume 10

Abstract: Abstract Background Purine receptors play roles in peripheral and central sensitization and are associated with migraine headache. We investigated the possibility that ATP plays a permissive role in the activation of AMPA receptors thus inducing Glu ... ...

Abstract	Abstract Background Purine receptors play roles in peripheral and central sensitization and are associated with migraine headache. We investigated the possibility that ATP plays a permissive role in the activation of AMPA receptors thus inducing Glu release from nerve terminals isolated from the rat trigeminal caudal nucleus (TCN). Methods Nerve endings isolated from the rat TCN were loaded with [3H]D-aspartic acid ([3H]D-ASP), layered into thermostated superfusion chambers, and perfused continuously with physiological medium, alone or with various test drugs. Radioactivity was measured to assess [3H]D-ASP release under different experimental conditions. Results Synaptosomal [3H]D-ASP spontaneous release was stimulated by ATP and to an even greater extent by the ATP analogue benzoylbenzoylATP (BzATP). The stimulation of [3H]D-ASP basal release by the purinergic agonists was prevented by the selective P2X7 receptor antagonist A438079. AMPA had no effect on basal [3H]D-ASP release, but the release observed when synaptosomes were exposed to AMPA plus a purinoceptor agonist exceeded that observed with ATP or BzATP alone. The selective AMPA receptor antagonist NBQX blocked this “excess” release. Co-exposure to AMPA and BzATP, each at a concentration with no release-stimulating effects, evoked a significant increase in [3H]D-ASP basal release, which was prevented by exposure to a selective AMPA antagonist. Conclusions P2X7 receptors expressed on glutamatergic nerve terminals in the rat TCN can mediate Glu release directly and indirectly by facilitating the activation of presynaptic AMPA receptors. The high level of glial ATP that occurs during chronic pain states can promote widespread release of Glu as well as can increase the function of AMPA receptors. In this manner, ATP contributes to the AMPA receptor activation involved in the onset and maintenance of the central sensitization associated with chronic pain.
Keywords	P2X7 receptor ; AMPA receptors ; Trigeminal caudal nucleus ; Synaptosomes ; [3H]D-aspartic acid release ; Central sensitization ; Medicine ; R
Subject code	610
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A proof-of-concept study on CGRP plasma levels of migraineurs during a 6-month treatment with ERENUMAB

Giuseppe Tringali / Catello Vollono / Paolo Calabresi / Pierluigi Navarra

The Journal of Headache and Pain, Vol 21, Iss 1, Pp 1-

2020 Volume 2

Abstract: Abstract The introduction of monoclonal antibodies (mAbs) against calcitonin-gene related peptide (CGRP) or CGRP receptors in the treatment of migraine raised concerns on the possible risks associated to the long-term inhibition of CGRP physiological ... ...

Abstract	Abstract The introduction of monoclonal antibodies (mAbs) against calcitonin-gene related peptide (CGRP) or CGRP receptors in the treatment of migraine raised concerns on the possible risks associated to the long-term inhibition of CGRP physiological functions. In this proof-of-concept study, we have measured the circulating levels of CGRP in 7 patients with high-frequency episodic migraine receiving the anti-CGRP receptor mAb erenumab for at least 6 months, to test the hypothesis that long-term blockade of CGRP receptors induces an increase in systemic CGRP levels via a classical up-regulation mechanism. Plasma CGRP levels were measured by a validated radioimmunoassay at baseline, and after 1 and 6 months of treatment with erenumab, 70 mg given sc every 4 weeks. We found (data expressed as the means ± SD): 38.34 ± 30.74 pg CGRP/ml of plasma at baseline, 38.19 ± 29.23 pg/ml after 1 month and 53.89 ± 28.03 pg/ml after 6 months of treatment. Thus, the average increase in plasma CGRP levels after 6 months of treatment was about + 40% compared to both baseline and 1-month treatments; such difference was not statistically significant because of high SD values in all groups. These preliminary findings need to be confirmed in larger, sufficiently powered experiments.
Keywords	CGRP ; CGRP receptor ; Monoclonal antibodies ; Erenumab ; Migraine ; Medicine ; R
Subject code	616
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Development of an UPLC-MS/MS Method for Quantitative Analysis of Clotrimazole in Human Plasma Samples

Lucia Lisi / Gabriella Maria Pia Ciotti / Pierluigi Navarra

Separations, Vol 7, Iss 62, p

2020 Volume 62

Abstract: An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the quantification of clotrimazole (CTZ) plasma levels after intravaginal administration of the drug given at approved dosages. Plasma samples were extracted by ... ...

Abstract	An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the quantification of clotrimazole (CTZ) plasma levels after intravaginal administration of the drug given at approved dosages. Plasma samples were extracted by liquid–liquid extraction and a single chromatographic run could be completed within about 2 min. The method was linear over the investigated range (0.488–250 ng/mL) with all the correlation coefficients, R 2 , greater than 0.9903. All data were in the range of ±15.0% with respect to the nominal concentration for high QC and medium QC, and in the range ±20% with respect to the nominal concentration for low QC. This rapid and sensitive method was validated and could be applied to human plasma samples from a healthy volunteer, showing that the assay is able to detect plasma concentrations of CTZ in the range of those found after the administration of the drug at approved dosages in the clinical setting.
Keywords	clotrimazole ; plasma ; UPLC/MS-MS ; bioequivalence ; intravaginal treatment ; Physics ; QC1-999 ; Chemistry ; QD1-999
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Optimal Solubility of Diclofenac β-Cyclodextrin in Combination with Local Anaesthetics for Mesotherapy Applications

Giuseppe Tringali / Pierluigi Navarra

Evidence-Based Complementary and Alternative Medicine, Vol

2017 Volume 2017

Abstract: Because of low injection volume, the recently marketed injectable solution of diclofenac in complex with β-cyclodextrin (Akis®, IBSA Farmaceutici Italia) is an ideal candidate for mesotherapy applications. In this study, we investigated the solubility of ...

Abstract	Because of low injection volume, the recently marketed injectable solution of diclofenac in complex with β-cyclodextrin (Akis®, IBSA Farmaceutici Italia) is an ideal candidate for mesotherapy applications. In this study, we investigated the solubility of Akis, 25 and 50 mg/kg, in combination with various local anaesthetics (lidocaine, mepivacaine, bupivacaine, levobupivacaine, and ropivacaine) at different concentrations in aqueous vehicles (normal saline, sterile water, or bicarbonate). Final injection mixtures were classified as limpid, turbid, or milky at visual analysis under standardized conditions. We found that (i) the use of sterile water for injections or normal saline as vehicles to dilute Akis in combination with whatever local anaesthetic normally results in milky solutions and therefore is not recommended; (ii) using bicarbonate, optimal solubility was obtained combining Akis with lidocaine, both 1 and 2%, or mepivacaine, both 1 and 2%, whereas solutions were turbid in combination with bupivacaine, levobupivacaine, or ropivacaine. Thus, we recommend that Akis is used in combination with lidocaine or mepivacaine in a bicarbonate vehicle.
Keywords	Other systems of medicine ; RZ201-999
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Perampanel inhibits calcitonin gene-related peptide release from rat brainstem in vitro

Giuseppe Tringali / Diego Currò / Pierluigi Navarra

The Journal of Headache and Pain, Vol 19, Iss 1, Pp 1-

2018 Volume 6

Abstract: Abstract Background Perampanel is a novel antiepileptic drug acting via non-competitive antagonism on glutamatergic AMPA receptors, and the subsequent inhibition of ion calcium influx. Since it was recently postulated that the antagonists of glutamate ... ...

Abstract	Abstract Background Perampanel is a novel antiepileptic drug acting via non-competitive antagonism on glutamatergic AMPA receptors, and the subsequent inhibition of ion calcium influx. Since it was recently postulated that the antagonists of glutamate receptors might play a role in the treatment of migraine, in this study we investigated the putative anti-migraine activity of perampanel in an in vitro animal model involving the static incubation of rat brainstem explants and the subsequent measurement of immune-reactive calcitonin gene-related peptide released into the incubation medium. Methods Acute rat brainstem explants were incubated in plain medium or in medium containing graded concentrations of perampanel. The release into the medium was assessed by radioimmunoassay either under baseline conditions or after stimulation by such secretagogues as high K+ concentrations, veratridine or capsaicin. Results We found that: 1) under baseline conditions perampanel, given in the range 0.01–100 μM, inhibited in a concentration-dependent manner calcitonin gene-related peptide’s release compared to controls; the decrease was statistically significant as from 10 μM; 2) a significant and consistent increase in calcitonin gene-related peptide’s secretion was induced by all depolarizing stimuli after 1 h of incubation; 3) under these conditions, calcitonin gene-related peptide’s release stimulated by 56 mM KCl was significantly reduced by perampanel from 0.1 μM onward, whereas secretion stimulated by veratridine was significantly reduced as from 1 μM; 4) on the contrary, perampanel had no effect on capsaicin-induced calcitonin gene-related peptide’s release up to 100 μM. Conclusions Here we provided preliminary in vitro evidence suggesting that perampanel might control pain transmission under conditions of activated trigeminal system, in a preclinical model mimicking the pathophysiology of human migraine.
Keywords	AMPA ; Brainstem ; Calcitonin gene-related peptide ; Glutammatergic ; Perampanel ; Innovative biotechnologies ; Medicine ; R
Subject code	571
Language	English
Publishing date	2018-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Neovascular Age-Related Macular Degeneration

Federico Ricci / Francesco Bandello / Pierluigi Navarra / Giovanni Staurenghi / Michael Stumpp / Marco Zarbin

International Journal of Molecular Sciences, Vol 21, Iss 8242, p

Therapeutic Management and New-Upcoming Approaches

2020 Volume 8242

Abstract: Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of ... ...

Abstract	Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease or reverses its course. Medical treatment of neovascular AMD experienced a significant advance due to the introduction of vascular endothelial growth factor inhibitors (anti-VEGF), which dramatically changed the prognosis of the disease. However, although anti-VEGF therapy has become the standard treatment for neovascular AMD, many patients do not respond adequately to this therapy or experience a slow loss of efficacy of anti-VEGF agents after repeated administration. Additionally, current treatment with intravitreal anti-VEGF agents is associated with a significant treatment burden for patients, caregivers, and physicians. New approaches have been proposed for treating neovascular AMD. Among them, designed ankyrin repeat proteins (DARPins) seem to be as effective as monthly ranibizumab, but with greater durability, which may enhance patient compliance with needed injections.
Keywords	age-related macular degeneration ; neovascular AMD ; neovascularization ; vascular endothelial growth factor ; anti-VEGF ; Ang-2 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation

Marta Chiavari / Gabriella Maria Pia Ciotti / Francesco Canonico / Fabio Altieri / Pedro Miguel Lacal / Grazia Graziani / Pierluigi Navarra / Lucia Lisi

International Journal of Molecular Sciences, Vol 21, Iss 8214, p

2020 Volume 8214

Abstract: The glioblastoma (GB) microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs) that are still poorly characterized. A potential role on the mechanisms regulating GAM activity might be played ...

Abstract	The glioblastoma (GB) microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs) that are still poorly characterized. A potential role on the mechanisms regulating GAM activity might be played by the endoplasmic reticulum protein ERp57/PDIA3 (protein disulfide-isomerase A3), the modulation of which has been reported in a variety of cancers. Moreover, by using The Cancer Genome Atlas database, we found that overexpression of PDIA3 correlated with about 55% reduction of overall survival of glioma patients. Therefore, we analyzed the expression of ERp57/PDIA3 using specimens obtained after surgery from 18 GB patients. Immunohistochemical analysis of tumor samples revealed ERp57/PDIA3 expression in GB cells as well as in GAMs. The ERp57/PDIA3 levels were higher in GAMs than in the microglia present in the surrounding parenchyma. Therefore, we studied the role of PDIA3 modulation in microglia–glioma interaction, based on the ability of conditioned media collected from human GB cells to induce the activation of microglial cells. The results indicated that reduced PDIA3 expression/activity in GB cells significantly limited the microglia pro-tumor polarization towards the M2 phenotype and the production of pro-inflammatory factors. Our data support a role of PDIA3 expression in GB-mediated protumor activation of microglia.
Keywords	PDIA3 ; STAT3 ; IL6 ; microglia ; glioma ; punicalagin ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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