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Future Perspectives of Cell-Based Research in Toxicology and Drug Discovery

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 9037

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Dr. Maja Katalinić

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Guest Editor

Institute for Medical Research and Occupational Health, Ksaverska c. 2, HR-10001 Zagreb, Croatia
Interests: in vitro toxicology; interaction of enzymes with reversible inhibitors; antidotes for treatment of organophosphorus compounds poisoning; influence of compounds on the cell level

Special Issue Information

Dear Colleagues,

A better selection of lead candidates for preclinical drug development, as well as toxicological studies or existing and new compounds, has become a non-negotiable necessity in recent years. In this sense, early, rapid and robust results unambiguously ranking compounds for their desirable and undesirable effects call for constant improvement in research techniques. Here, cell-based in vitro toxicology is the most promising method for overcoming the criticised use of animals in toxicological studies. To be more precise, cell-based assays have emerged as the mainframe of early safety evaluation studies and proved efficacious for the assessment of organ toxicities, among other characteristics. In other words, by the simple addition of cell-based assay identification of specific molecular targets of the tested compounds’ unwanted actions or even the identification of novel cell targets, extending the proposed therapeutic approach would be possible. This approach helps reduce the risk of missing critical information, which often proves costly in later stages of development. Furthermore, the cell culture techniques and media available on the market today allow for almost all cell types, of both animal and human origin, to be effectively grown using both 2D and 3D techniques. Moreover, the possible utilisation of human cells in research could benefit risk assessments for human situations and overcome potential cross-species differences.

In this context, we encourage the submission of manuscripts, both original research papers and review papers, presenting novel findings of compound action on the molecular cell level while considering future perspectives in toxicology and drug discovery.

Dr. Maja Katalinić
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

primary cells
cell culture
antidotes
xenobiotics
toxicity
mechanism of action
side-effects
organophosphorus compounds

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Published Papers (5 papers)

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Research

27 pages, 2446 KiB

Open AccessArticle

Intermolecular Electrostatic Interactions in Cytochrome c Protein Monolayer on Montmorillonite Alumosilicate Surface: A Positive Cooperative Effect

by Svetlana H. Hristova and Alexandar M. Zhivkov

Int. J. Mol. Sci. 2024, 25(13), 6834; https://doi.org/10.3390/ijms25136834 - 21 Jun 2024

Viewed by 910

Abstract

Montmorillonite (MM) crystal nanoplates acquire anticancer properties when coated with the mitochondrial protein cytochrome c (cytC) due to the cancer cells’ capability to phagocytize cytC-MM colloid particles. The introduced exogenous cytC initiates apoptosis: an irreversible cascade of biochemical reactions leading to cell death. In the present research, we investigate the organization of the cytC layer on the MM surface by employing physicochemical and computer methods—microelectrophoresis, static, and electric light scattering—to study cytC adsorption on the MM surface, and protein electrostatics and docking to calculate the local electric potential and Gibbs free energy of interacting protein globules. The found protein concentration dependence of the adsorbed cytC quantity is nonlinear, manifesting a positive cooperative effect that emerges when the adsorbed cytC globules occupy more than one-third of the MM surface. Computer analysis reveals that the cooperative effect is caused by the formation of protein associates in which the cytC globules are oriented with oppositely charged surfaces. The formation of dimers and trimers is accompanied by a strong reduction in the electrostatic component of the Gibbs free energy of protein association, while the van der Waals component plays a secondary role. Full article

(This article belongs to the Special Issue Future Perspectives of Cell-Based Research in Toxicology and Drug Discovery)

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19 pages, 1567 KiB

Open AccessArticle

Profiling Novel Quinuclidine-Based Derivatives as Potential Anticholinesterase Drugs: Enzyme Inhibition and Effects on Cell Viability

by Suzana Žunec, Donna Vadlja, Alma Ramić, Antonio Zandona, Nikola Maraković, Iva Brekalo, Ines Primožič and Maja Katalinić

Int. J. Mol. Sci. 2024, 25(1), 155; https://doi.org/10.3390/ijms25010155 - 21 Dec 2023

Cited by 1 | Viewed by 1237

Abstract

The cholinergic system, relying on the neurotransmitter acetylcholine (ACh), plays a significant role in muscle contraction, cognition, and autonomic nervous system regulation. The enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, responsible for hydrolyzing ACh, can fine-tune the cholinergic system’s activity and are, therefore, excellent pharmacological targets to address a range of medical conditions. We designed, synthesized, and profiled 14 N-alkyl quaternary quinuclidines as inhibitors of human AChE and BChE and analyzed their impact on cell viability to assess their safety in the context of application as potential therapeutics. Our results showed that all of the 14 tested quinuclidines inhibited both AChE and BChE in the micromolar range (K_i = 0.26 − 156.2 μM). The highest inhibition potency was observed for two bisquaternary derivatives, 7 (1,1′-(decano)bis(3-hydroxyquinuclidinium bromide)) and 14 (1,1′-(decano)bis(3-hydroxyiminoquinuclidinium bromide)). The cytotoxic effect within 7–200 μM was observed only for monoquaternary quinuclidine derivatives, especially those with the C12–C16 alkyl chain. Further analysis revealed a time-independent mechanism of action, significant LDH release, and a decrease in the cells’ mitochondrial membrane potential. Taking all results into consideration, we can confirm that a quinuclidine core presents a good scaffold for cholinesterase binding and that two bisquaternary quinuclidine derivatives could be considered as candidates worth further investigations as drugs acting in the cholinergic system. On the other hand, specific cell-related effects probably triggered by the free long alkyl chain in monoquaternary quinuclidine derivatives should not be neglected in future N-alkyl quaternary quinuclidine derivative structure refinements. Such an effect and their potential to interact with other specific targets, as indicated by a pharmacophore model, open up a new perspective for future investigations of these compounds’ scaffold in the treatment of specific conditions and diseases other than cholinergic system-linked disorders. Full article

(This article belongs to the Special Issue Future Perspectives of Cell-Based Research in Toxicology and Drug Discovery)

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16 pages, 2245 KiB

Open AccessArticle

Vasodilating Effects of Antispasmodic Agents and Their Cytotoxicity in Vascular Smooth Muscle Cells and Endothelial Cells—Potential Application in Microsurgery

by Misato Ueda, Yasuki Hirayama, Haruo Ogawa, Tadashi Nomura, Hiroto Terashi and Shunsuke Sakakibara

Int. J. Mol. Sci. 2023, 24(13), 10850; https://doi.org/10.3390/ijms241310850 - 29 Jun 2023

Viewed by 1951

Abstract

This study aimed to elucidate the vasodilatory effects and cytotoxicity of various vasodilators used as antispasmodic agents during microsurgical anastomosis. Rat smooth muscle cells (RSMCs) and human coronary artery endothelial cells (HCAECs) were used to investigate the physiological concentrations and cytotoxicity of various vasodilators (lidocaine, papaverine, nitroglycerin, phentolamine, and orciprenaline). Using a wire myograph system, we determined the vasodilatory effects of each drug in rat abdominal aortic sections at the concentration resulting in maximal vasodilation as well as at the surrounding concentrations 10 min after administration. Maximal vasodilation effect 10 min after administration was achieved at the following concentrations: lidocaine, 35 mM; papaverine, 0.18 mM; nitroglycerin, 0.022 mM; phentolamine, 0.11 mM; olprinone, 0.004 mM. The IC₅₀ for lidocaine, papaverine, and nitroglycerin was measured in rat abdominal aortic sections, as well as in RSMCs after 30 min and in HCAECs after 10 min. Phentolamine and olprinone showed no cytotoxicity towards RSMCs or HCAECs. The concentrations of the various drugs required to achieve vasodilation were lower than the reported clinical concentrations. Lidocaine, papaverine, and nitroglycerin showed cytotoxicity, even at lower concentrations than those reported clinically. Phentolamine and olprinone show antispasmodic effects without cytotoxicity, making them useful candidates for local administration as antispasmodics. Full article

(This article belongs to the Special Issue Future Perspectives of Cell-Based Research in Toxicology and Drug Discovery)

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13 pages, 1631 KiB

Open AccessArticle

Impact of Deoxynivalenol and Zearalenone as Single and Combined Treatment on DNA, Cell Cycle and Cell Proliferation in HepG2 Cells

by Ana-Marija Domijan, Klara Hercog, Martina Štampar, Goran Gajski, Marko Gerić, Marijana Sokolović and Bojana Žegura

Int. J. Mol. Sci. 2023, 24(4), 4082; https://doi.org/10.3390/ijms24044082 - 17 Feb 2023

Cited by 6 | Viewed by 2192

Abstract

The study aimed to investigate toxicity and the mechanism of toxicity of two Fusarium mycotoxins, deoxynivalenol (DON) and zearalenone (ZEA). DON and ZEA were applied to HepG2 cells as single compounds and in combination at low environmentally relevant concentrations. HepG2 cells were exposed to DON (0.5, 1, and 2 µM), ZEA (5, 10, and 20 µM) or their combinations (1 µM DON + 5 µM ZEA, 1 µM DON + 10 µM ZEA and 1 µM DON + 20 µM ZEA) for 24 h and cell viability, DNA damage, cell cycle and proliferation were assessed. Both mycotoxins reduced cell viability, however, combined treatment with DON and ZEA resulted in higher reduction of cell viability. DON (1 µM) induced primary DNA damage, while DON (1 µM) in combination with higher ZEA concentrations showed antagonistic effects compared to DON alone at 1 µM. DON arrested HepG2 cells in G2 phase and significantly inhibited cell proliferation, while ZEA had no significant effect on cell cycle. The combined treatment with DON and ZEA arrested cells in G2 phase to a higher extend compared to treatment with single mycotoxins. Potentiating effect observed after DON and ZEA co-exposure at environmentally relevant concentrations indicates that in risk assessment and setting governments’ regulations, mixtures of mycotoxins should be considered. Full article

(This article belongs to the Special Issue Future Perspectives of Cell-Based Research in Toxicology and Drug Discovery)

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19 pages, 3357 KiB

Open AccessArticle

Adverse Toxic Effects of Tyrosine Kinase Inhibitors on Non-Target Zebrafish Liver (ZFL) Cells

by Katja Kološa, Bojana Žegura, Martina Štampar, Metka Filipič and Matjaž Novak

Int. J. Mol. Sci. 2023, 24(4), 3894; https://doi.org/10.3390/ijms24043894 - 15 Feb 2023

Cited by 5 | Viewed by 2033

Abstract

Over the past 20 years, numerous tyrosine kinase inhibitors (TKIs) have been introduced for targeted therapy of various types of malignancies. Due to frequent and increasing use, leading to eventual excretion with body fluids, their residues have been found in hospital and household wastewaters as well as surface water. However, the effects of TKI residues in the environment on aquatic organisms are poorly described. In the present study, we investigated the cytotoxic and genotoxic effects of five selected TKIs, namely erlotinib (ERL), dasatinib (DAS), nilotinib (NIL), regorafenib (REG), and sorafenib (SOR), using the in vitro zebrafish liver cell (ZFL) model. Cytotoxicity was determined using the MTS assay and propidium iodide (PI) live/dead staining by flow cytometry. DAS, SOR, and REG decreased ZFL cell viability dose- and time-dependently, with DAS being the most cytotoxic TKI studied. ERL and NIL did not affect viability at concentrations up to their maximum solubility; however, NIL was the only TKI that significantly decreased the proportion of PI negative cells as determined by the flow cytometry. Cell cycle progression analyses showed that DAS, ERL, REG, and SOR caused the cell cycle arrest of ZFL cells in the G0/G1 phase, with a concomitant decrease of cells in the S-phase fraction. No data could be obtained for NIL due to severe DNA fragmentation. The genotoxic activity of the investigated TKIs was evaluated using comet and cytokinesis block micronucleus (CBMN) assays. The dose-dependent induction of DNA single strand breaks was induced by NIL (≥2 μM), DAS (≥0.006 μM), and REG (≥0.8 μM), with DAS being the most potent. None of the TKIs studied induced micronuclei formation. These results suggest that normal non-target fish liver cells are sensitive to the TKIs studied in a concentration range similar to those previously reported for human cancer cell lines. Although the TKI concentrations that induced adverse effects in exposed ZFL cells are several orders of magnitude higher than those currently expected in the aquatic environment, the observed DNA damage and cell cycle effects suggest that residues of TKIs in the environment may pose a hazard to non-intentionally exposed organisms living in environments contaminated with TKIs. Full article

(This article belongs to the Special Issue Future Perspectives of Cell-Based Research in Toxicology and Drug Discovery)

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