Anti-Diarrheal Drug Repositioning in Tumour Cell Cytotoxicity

Elloumi-Mseddi, Jihene; Msalbi, Dhouha; Fakhfakh, R.; Aifa, Sami

doi:10.2174/1871520619666190118120030

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…Although 22 molecules inhibited the [S¡R] transition at 1 M, microscopic analysis of the phenotype indicated that some of them were parasiticidal (and, thus, unlikely to have any direct effect on the egress/invasion process). Molecules inhibiting the [S¡R] transition only at 3 M and 10 M were not considered for further experiments since at higher concentrations the observed inhibition could have been due to general cytotoxicity on merozoite viability (35,36).…”

Section: Resultsmentioning

confidence: 99%

Whole-Cell Phenotypic Screening of Medicines for Malaria Venture Pathogen Box Identifies Specific Inhibitors of Plasmodium falciparum Late-Stage Development and Egress

Patra

Hingamire

Belekar

et al. 2020

Antimicrob Agents Chemother

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We report a systematic, cellular phenotype-based antimalarial screening of the Medicines for Malaria Venture Pathogen Box collection, which facilitated the identification of specific blockers of late-stage intraerythrocytic development of Plasmodium falciparum. First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (50% effective concentration [EC50] ≤ 10 μM), which included 62 additional molecules over previously known antimalarial candidates from the Pathogen Box. We identified 90 molecules with EC50 of ≤1 μM, which had significant effect on the ring-trophozoite transition, while 9 molecules inhibited the trophozoite-schizont transition and 21 molecules inhibited the schizont-ring transition (with ≥50% parasites failing to proceed to the next stage) at 1 μM. We therefore rescreened all 173 molecules and validated hits in microscopy to prioritize 12 hits as selective blockers of the schizont-ring transition. Seven of these molecules inhibited the calcium ionophore-induced egress of Toxoplasma gondii, a related apicomplexan parasite, suggesting that the inhibitors may be acting via a conserved mechanism which could be further exploited for target identification studies. We demonstrate that two molecules, MMV020670 and MMV026356, identified as schizont inhibitors in our screens, induce the fragmentation of DNA in merozoites, thereby impairing their ability to egress and invade. Further mechanistic studies would facilitate the therapeutic exploitation of these molecules as broadly active inhibitors targeting late-stage development and egress of apicomplexan parasites relevant to human health.

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Section: Resultsmentioning

confidence: 99%

Whole-Cell Phenotypic Screening of Medicines for Malaria Venture Pathogen Box Identifies Specific Inhibitors of Plasmodium falciparum Late-Stage Development and Egress

Patra

Hingamire

Belekar

et al. 2020

Antimicrob Agents Chemother

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“…In these activities, the blocking of the STAT3 pathways plays an important role. Nifuroxazide can be effective as prophylaxis or second-line therapy for aGvHD (4)(5)(6)(7)(8)(28)(29)(30). It can be assumed that this old drug will find a new application in medicine.…”

Section: Resultsmentioning

confidence: 99%

Safety of oral nifuroxazide – analysis of data from a spontaneous reporting system

Karłowicz-Bodalska¹,

Głowacka²,

Boszkiewicz³

et al. 2019

Acta Poloniae Pharmaceutica - Drug Research

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Nifuroxazide (4-hydroxy-benzoic acid; 2-[(5nitro-2-furanyl)methylene]hydrazide) is a chemotherapeutic agent belonging to the nitrofuran family. Indications for its use are acute and chronic bacterial diarrhea and other diseases with diarrhea (1). The drug has local antibacterial activity against some Gram-positive bacteria of the genus Staphylococcus and Gram-negative bacteria from the Enterobacteriaceae family: Yersinia spp., Escherichia spp., Enterobacter spp., Klebsiella spp. and Salmonella spp. It does not affect the bacteria Proteus vulgaris, Proteus mirabilis and Pseudomonas aeruginosa (1-3). Recently, attention has been paid to its antitumor potential in neuroblastoma, multiple myeloma, colorectal and breast cancer, efficacy in the treatment of graft-versus-host disease and nephroprotection in diabetes (4-10). The exact mechanism of action of nifuroxazide has not yet been identified. It probably has an inhibitory effect on dehydrogenase activity and protein synthesis in bacterial cells. Aldehyde dehydrogenase (ALDH) is responsible for the bioactivation of this prodrug. It has been found that nifuroxazide is a potent inhibitor of the Janus kinase 2 pathways and transcription factor 3 (JAK2/STAT3). It also has direct effects on oxidative stress and apoptosis (2, 4-6). Frequent self-administration of this drug by patients makes it necessary to pay attention to selfmedication, which in accordance with the guidelines of the World Health Organization is defined as ìusing medication by the consumer to treat signs/symptoms or minor health problems, recognized as such by themselvesî. In practice, this term also includes treatment by family members or friends, mainly, when the child is being treated (11). It should be responsible and safe, especially considering that diarrhea, in particular, acute diarrhea, is a serious problem of primary and hospital care. Itís serious complications, such as electrolyte disturbances, oligovolemic shock and even death, are dangerous especially for newborns, babies, small children and elderly people, due to their susceptibility to dehydration (12, 13). The fact that adverse effects inevitably accompany the desired therapeutic effects

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“…Although 29 molecules inhibited [S→R] transition at 1 µM, microscopic analysis of phenotype indicated that some of them were parasiticidal (and thus unlikely to have any direct effect on the egress/invasion process). Molecules inhibiting [S→R] transition only at 3 µM and 10 µM were not consider for further study since at higher concentrations the observed inhibition can be due to general cytotoxicity on merozoite viability 43–44 .…”

Section: Resultsmentioning

confidence: 99%

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

Patra

Hingamire

Belekar

et al. 2019

Preprint

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30We report a systematic, cellular phenotype-based antimalarial screening of the MMV Pathogen Box 31 collection, which facilitated the identification of specific blockers of late stage intraerythrocytic 32 Plasmodium falciparum maturation. First, from standard growth inhibition asays, we discovered 62 33 additional antimalarials (EC 50 ≤ 10µM) over previously known antimalarial candidates from Pathogen 34 Box. A total of 90 potent molecules (EC 50 ≤ 1µM) were selected for evaluating their stage-specific 35 effects during the intra-erythrocytic development of P. falciparum. None of these molecules had 36 significant effect on ring-trophozoite transition, 10 molecules inhibited trophozoite-schizont transition, 37 and 21 molecules inhibited schizont-ring transition at 1µM. These compounds were further validated 38 in secondary assays by flow cytometry and microscopic imaging of treated cells to prioritize 12 39 molecules as potent and selective blockers of schizont-ring transition. Seven of these were found to 40 strongly inhibit calcium ionophore induced egress of Toxoplasma gondii, a related apicomplexan 41 parasite, suggesting that the inhibitors may be acting via similar mechanism in the two parasites, 42 which can be further exploited for target identification studies. Two of these molecules, with previously 43 unknown mechanism of action, MMV020670 and MMV026356, were found to induce fragmentation of 44 DNA in developing merozoites. Further mechanistic studies would facilitate therapeutic exploitation of 45 these molecules as broadly active inhibitors targeting development and egress of apicomplexan 46 parasites relevant to human health. 47 48 49 Despite technological advancements and improved knowledge on disease manifestation and 69 pathogen biology, progress in therapeutic development has been slower than expected for human 70 infectious diseases affecting the developing world. In addition to limited financial prospects, 71 pharmaceutical companies remain under significant pressure to address high attrition rates. In this 72 context, repurposing of old drugs is becoming a viable alternative through the exploitation of known 73 compounds with established mechanisms thereby shortening the time window between efficacy 74 testing to pharmacophore optimization 1-3 to eventual application. In recent efforts to speed up the 75 process of drug development against various pathogenic diseases, a collaborative model of public-76 private partnerships (PPPs) facilitated through Medicines for Malaria Venture (MMV: mmv.org) was 77 formed. This resulted in well-characterized drug-like small molecule libraries being made accessible 78 to academics worldwide, for the purpose of identifying novel bioactivities against various tropical 79 disease pathogens and conducting focused mechanistic studies. In 2015, the consortium launched 80 the open access "Pathogen Box" consisting of 400 drug-like small molecules, included 26 reference 81 compounds, with confirmed bioactivity against at least one of the neglected disease pathogens ...

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Anti-Diarrheal Drug Repositioning in Tumour Cell Cytotoxicity

Cited by 5 publications

References 24 publications

Whole-Cell Phenotypic Screening of Medicines for Malaria Venture Pathogen Box Identifies Specific Inhibitors of Plasmodium falciparum Late-Stage Development and Egress

Whole-Cell Phenotypic Screening of Medicines for Malaria Venture Pathogen Box Identifies Specific Inhibitors of Plasmodium falciparum Late-Stage Development and Egress

Safety of oral nifuroxazide – analysis of data from a spontaneous reporting system

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

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