Assessment of in vitro cytotoxic and genotoxic activities of some trimethoprim conjugates

Bayülken, Devrim Güzel; Bostancıoğlu, Rakibe Beklem; Koparal, Ayşe Tansu; Tüylü, Berrin Ayaz; Dağ, Aydan; Benkli, Kadriye

doi:10.1007/s10616-018-0187-7

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…Indeed, our in vitro study showed that a high dose of TMP could also inhibit VEGF mRNA expression (Figure S1). High doses of TMP can induce cell toxicity [20], thus modifying VEGF mRNA expression under hypoxia condition. Therefore, administration of high-dose TMP together with DHFR(DD)-Flt23k gene delivery may act synergistically to suppress VEGF at both the transcriptional level and the posttranslational level.…”

Section: Discussionmentioning

confidence: 99%

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization

et al. 2020

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Gene therapies that chronically suppress vascular endothelial growth factor (VEGF) represent a new approach for managing retinal vascular leakage and neovascularization. However, constitutive suppression of VEGF in the eye may have deleterious side effects. Here, we developed a novel strategy to introduce Flt23k, an intraceptor that binds intracellular VEGF, fused to the destabilizing domain (DD) of Escherichia coli dihydrofolate reductase (DHFR) into the retina. The expressed DHFR(DD)-Flt23k fusion protein is degraded unless "switched on" by administering a stabilizer; in this case, the antibiotic trimethoprim (TMP). Cells transfected with the DHFR(DD)-Flt23k construct expressed the fusion protein at levels correlated with the TMP dose. Stabilization of the DHFR(DD)-Flt23k fusion protein by TMP was able to inhibit intracellular VEGF in hypoxic cells. Intravitreal injection of selfcomplementary adeno-associated viral vector (scAAV)-DHFR(DD)-Flt23k and subsequent administration of TMP resulted in tunable suppression of ischemia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy (OIR). Hence, our study suggests a promising novel approach for the treatment of retinal neovascularization.

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Section: Discussionmentioning

confidence: 99%

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization

et al. 2020

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“…TMP treatment increased the frequency of micronuclei and sister chromatid exchanges (SCE) in human cells in vitro (10). Additionally, an increase in micronuclei frequency was observed using the cytokinesis-block micronucleus (CBMN) assay (11,12). By using the same technique, minor increases in micronuclei and SCE were found following SMX therapy.…”

Section: Trimethoprimmentioning

confidence: 97%

In VivoGenotoxicity and Cytotoxicity Kinetics of Trimethoprim Sulfamethoxazole in Well-nourished and Undernourished Young Rats

ORTIZ-MUÑIZ,

CERVANTES-RÍOS,

SORIANO-CORREA

et al. 2024

In Vivo

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Background/Aim: Undernutrition is a serious health problem prevalent in poor countries, affecting millions of people worldwide, especially young children, pregnant women, and sick elderly individuals. This condition increases vulnerability to infections, leading to widespread use of antibiotic treatments in undernourished populations. The objective of the present study was to determine the in vivo genotoxic and cytotoxic effects of trimethoprimsulfamethoxazole (TMP-SMX) treatment according to nutritional conditions. Materials and Methods: The effects of TMP-SMX treatment were measured by analyzing the kinetics of micronucleated reticulocytes (MN-RET) induced in the peripheral blood of young, well-nourished (WN) and undernourished (UN) rats. Results: In the WN group, two distinct peaks of MN-RET were observed, while the UN group had a significantly higher basal frequency of MN-RET compared to the WN group and only a later peak. Reticulocyte (RET) frequency slightly decreased in WN, indicating a poor cytotoxic effect. In contrast, in the UN, the treatment caused a significant increase in RET frequency. The results indicate that SMX's aromaticity index decreases when formed with TMP, suggesting potentially fewer toxic effects. Conclusion: In vivo TMP-SMX produces two MN-RET induction peaks in WN animals, indicating two DNA damage induction mechanisms and consequent micronucleusproduction. The UN rats did not display the two peaks, indicating that the first MN induction mechanism did not occur in UN, possibly due to pharmacokinetic effects, decreased metabolism or effects on cell proliferation. TMP-SMX has a slight cytotoxic effect on WN. In contrast, in the UN, the antibiotic treatment seems to favor early erythropoiesis.

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“…Trimethoprim is generally well-tolerated at the dosages used, and studies comparing trimethoprim to co-trimoxazole have shown that skin rashes and gastrointestinal upset are less common when trimethoprim is used alone. (14) An in vitro study revealed that trimethoprim and its conjugates exert a cytotoxic effect on cancer cells and induce cancer cell apoptosis (15). Furthermore, the trimethoprim structure exhibits structural similarity and common pharmacophoric features with colchicine and the combretastatins (Fig.…”

Section: Introductionmentioning

confidence: 99%

Computational repurposing of Trimethoprim: molecular docking and molecular dynamics simulation studies suggest a potential inhibition of colchicine-binding site.

Osama,

Shahin,

Elrazaz

et al. 2023

Preprint

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Cancer is a major global health concern, and its incidence is projected to rise in the coming years. Drug repurposing, the identification of new uses for existing drugs, offers a promising approach to accelerating the development of potent and less toxic anti-cancer agents. This in silico study explored the possible repurposing of trimethoprim, an approved synthetic antimicrobial, as a colchicine-binding site (CBS) inhibitor using molecular docking and molecular dynamics (MD) simulations. Trimethoprim shares structural similarities and pharmacophoric features with colchicine and the combretastatins, potent antimitotic agents that target the CBS. The docking results showed that trimethoprim achieved a good binding affinity to the CBS, with an average CDOCKER_ENERGY of -33.75 kcal/mol. The MD simulations (100 nanoseconds) confirmed the stability of the trimethoprim-tubulin complex, with a root mean square deviation (RMSD) of less than 2.5 Å for the protein backbone. The root mean square fluctuation (RMSF) of the binding site residues increased, indicating their increased flexibility. The radius of gyration (Rg) also increased within acceptable limits, suggesting that the protein unfolds to accommodate trimethoprim binding. The binding energy calculated using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach was − 27.3 kcal/mol, which further confirms the docking results. Overall, the findings of this study provide preliminary evidence that trimethoprim has the potential to be repurposed as a CBS inhibitor. Further in vitro and in vivo studies are needed to validate its efficacy and safety as a potential anti-cancer agent.

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Assessment of in vitro cytotoxic and genotoxic activities of some trimethoprim conjugates

Cited by 8 publications

References 28 publications

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization

In VivoGenotoxicity and Cytotoxicity Kinetics of Trimethoprim Sulfamethoxazole in Well-nourished and Undernourished Young Rats

Computational repurposing of Trimethoprim: molecular docking and molecular dynamics simulation studies suggest a potential inhibition of colchicine-binding site.

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