Anticancer active trifluoromethylated fused triazinones are safe for early-life stages of zebrafish (<i>Danio rerio</i>) and reveal a proapoptotic action

Sztanke, Małgorzata; Rzymowska, Jolanta; Sztanke, Krzysztof

doi:10.1080/14756366.2020.1865944

Cited by 6 publications

(9 citation statements)

References 34 publications

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“…Additionally, by examining the influence of the lipophilicity of all the compounds on their toxicity, strong correlations between the log k w values [1] (determined on two various columns) and the LC 50 values of the compounds were confirmed, which indicates that the toxicity of novel isopropylated congeners towards developing zebrafish enhances with an increase in their lipophilicity (Figure 3). These observations are consistent with those reported in previous studies on zebrafish embryos [15][16][17]. In groups exposed to the compounds/pemetrexed at a 150 μM concentration, the mortality was 100%.…”

Section: The Effect Of the Tested Isopropylated Fused Azaisocytosine-...supporting

confidence: 92%

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Anti-Tumor Active Isopropylated Fused Azaisocytosine-Containing Congeners Are Safe for Developing Danio rerio as Well as Red Blood Cells and Activate Apoptotic Caspases in Human Breast Carcinoma Cells

2022

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New isopropylated fused azaisocytosine-containing congeners (I–VI) have previously been reported as promising anticancer drug candidates, so further research on these molecules in the preclinical development phase is fully justified and necessary. For this reason, in the present paper, we assess the toxicity/safety profiles of all the compounds using Danio rerio and red blood cell models, and examine the effect of the most selective congeners on the activation of apoptotic caspases in cancer and normal cells. In order to evaluate the effect of each molecule on the development of zebrafish embryos/larvae and to select the safest compounds for further study, various phenotypic parameters (i.e., mortality, hatchability, heart rate, heart oedema, yolk sac utilization, swim bladder development and body shape) were observed, and the half maximal lethal concentration, the maximal non-lethal concentration and no observed adverse effect concentration for each compound were established. The effect of all the isopropylated molecules was compared to that of an anticancer agent pemetrexed. The lipophilicity-dependent structure–toxicity correlations were also determined. To establish the possible interaction of the compounds with red blood cells, an ex vivo hemolysis test was performed. It was shown that almost all of the investigated isopropylated congeners have no adverse phenotypic effect on zebrafish development during five-day exposure at concentrations up to 50 μM (I–III) or up to 20 μM (IV–V), and that they are less toxic for embryos/larvae than pemetrexed, demonstrating their safety. At the same time, all the molecules did not adversely affect the red blood cells, which confirms their very good hemocompatibility. Moreover, they proved to be activators of apoptotic caspases, as they increased caspase-3, -7 and -9 levels in human breast carcinoma cells. The conducted research allows us to select—from among the anticancer active drug candidates—compounds that are safe for developing zebrafish and red blood cells, suitable for further in vivo pharmacological tests.

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Section: The Effect Of the Tested Isopropylated Fused Azaisocytosine-...supporting

confidence: 92%

“…Acute toxicity studies were based on the OECD (Organization for Economic Cooperation and Development) guidelines for the testing of chemicals [31], and were performed according to the modified procedures described earlier [15,32].…”

Section: Zebrafish Embryo Acute Toxicity Studiesmentioning

confidence: 99%

Anti-Tumor Active Isopropylated Fused Azaisocytosine-Containing Congeners Are Safe for Developing Danio rerio as Well as Red Blood Cells and Activate Apoptotic Caspases in Human Breast Carcinoma Cells

2022

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“…The compounds 8, 10, 11, 17, and 19 exhibited the clearly higher antiproliferative effects in cancer cells than in normal cells [19][20][21]. In addition, the compounds 7, 8, and 10-12 were shown to be safer for the early life stages of Danio rerio than pemetrexed [22]. Due to the important pharmacological activity, all these organic substances require more thorough and extensive research on modeling their pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 99%

Predicting Pharmacokinetic Properties of Potential Anticancer Agents via Their Chromatographic Behavior on Different Reversed Phase Materials

Janicka

Mycka

Sztanke

et al. 2021

IJMS

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The Quantitative Structure-Activity Relationship (QSAR) methodology was used to predict biological properties, i.e., the blood–brain distribution (log BB), fraction unbounded in the brain (fu,brain), water-skin permeation (log Kp), binding to human plasma proteins (log Ka,HSA), and intestinal permeability (Caco-2), for three classes of fused azaisocytosine-containing congeners that were considered and tested as promising drug candidates. The compounds were characterized by lipophilic, structural, and electronic descriptors, i.e., chromatographic retention, topological polar surface area, polarizability, and molecular weight. Different reversed-phase liquid chromatography techniques were used to determine the chromatographic lipophilicity of the compounds that were tested, i.e., micellar liquid chromatography (MLC) with the ODS-2 column and polyoxyethylene lauryl ether (Brij 35) as the effluent component, an immobilized artificial membrane (IAM) chromatography with phosphatidylcholine column (IAM.PC.DD2) and chromatography with end-capped octadecylsilyl (ODS) column using aqueous solutions of acetonitrile as the mobile phases. Using multiple linear regression, we derived the statistically significant quantitative structure-activity relationships. All these QSAR equations were validated and were found to be very good. The investigations highlight the significance and possibilities of liquid chromatographic techniques with three different reversed-phase materials and QSARs methods in predicting the pharmacokinetic properties of our important organic compounds and reducing unethical animal testing.

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“…Several other advantages of Zebrafish are, they have a genome that is similar to the human genome, high reproductive ability, structural resemblances with vertebrates, embryo's optical transparency, high in external embryonic development, good characterized behaviour and small in size. Mainly it is not expensive so it is a unique animal model for assessing the new drug's toxicity [13]. Lichens are the symbiotic associated organism, which consists of both algae, the photobiont and Fungi, the mycobiont.…”

Section: Introductionmentioning

confidence: 99%

Embryotoxicity and Teratogenic Effects of Parmotrema Tinctorum (Nyl) Hale on Zebrafish (Danio Rerio) and Cytotoxic Activity of Lichen Extract on Hek293t Cell Line

Shenbagam¹

2021

ITII

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Parmotrema tinctorum (Nyl) Hale an edible lichen, used as a spice and flavouring agent for meat and vegetable preparations by ethnic groups in India and Nepal. In Zebrafish embryos and larva, the therapeutic applications of P.tinctorum widely reported. However the teratogenic effects not reported. This study was aimed to examine the toxicity of P.tinctorum on the promising model for toxicity research, the Zebrafish, because their genetic structure is more similar to human beings. Additionally, we have demonstrated a toxic effect of P.tinctorum extract on the human normal cell line (HEK293T) by MTT assay. The methanol extract of P.tinctorum was extracted by Soxhlet and for embryotoxicity and teratogenicity activities, we use different concentrations (50µg/ml – 200µg/ml) of lichen extracts on twelve selected fertilized Zebrafish embryos. The extract did not exhibit any effect on Zebrafish Survival rate, hatching rate, heartbeat and teratogenicity which was similar to control groups. To conclude that, methanol extract of P.tinctorum is found to have a nontoxic property to zebrafish embryo and human normal cell line (HEK293T) and suggests that this might be safe for consumption

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Anticancer active trifluoromethylated fused triazinones are safe for early-life stages of zebrafish (Danio rerio) and reveal a proapoptotic action

Cited by 6 publications

References 34 publications

Anti-Tumor Active Isopropylated Fused Azaisocytosine-Containing Congeners Are Safe for Developing Danio rerio as Well as Red Blood Cells and Activate Apoptotic Caspases in Human Breast Carcinoma Cells

Anti-Tumor Active Isopropylated Fused Azaisocytosine-Containing Congeners Are Safe for Developing Danio rerio as Well as Red Blood Cells and Activate Apoptotic Caspases in Human Breast Carcinoma Cells

Predicting Pharmacokinetic Properties of Potential Anticancer Agents via Their Chromatographic Behavior on Different Reversed Phase Materials

Embryotoxicity and Teratogenic Effects of Parmotrema Tinctorum (Nyl) Hale on Zebrafish (Danio Rerio) and Cytotoxic Activity of Lichen Extract on Hek293t Cell Line

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