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Article ; Online: Jozimine A

Damiescu, Roxana / Yücer, Rümeysa / Klauck, Sabine M / Bringmann, Gerhard / Efferth, Thomas / Dawood, Mona

International journal of molecular sciences

2024 Volume 25, Issue 6

Abstract: Naphthylisoquinoline (NIQ) alkaloids are rising as a promising class of secondary metabolites with pharmaceutical potential. NF-κB has already been recognized as a significant modulator of cancer proliferation and drug resistance. We have previously ... ...

Abstract	Naphthylisoquinoline (NIQ) alkaloids are rising as a promising class of secondary metabolites with pharmaceutical potential. NF-κB has already been recognized as a significant modulator of cancer proliferation and drug resistance. We have previously reported the mechanisms behind the cytotoxic effect of dioncophylline A, an NIQ monomer, in leukemia cells. In the current study, we have investigated the cytotoxic effect of jozimine A
MeSH term(s)	Humans ; Alkaloids/pharmacology ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Endothelial Cells ; Leukemia/drug therapy ; Molecular Docking Simulation ; NF-kappa B/pharmacology
Chemical Substances	Alkaloids ; Antineoplastic Agents ; NF-kappa B ; jozimine A2
Language	English
Publishing date	2024-03-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25063087
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Article ; Online: The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells.

Zhou, Min / Boulos, Joelle C / Klauck, Sabine M / Efferth, Thomas

Cell biology and toxicology

2023 Volume 39, Issue 6, Page(s) 2971–2997

Abstract: ... that cell death and survival as well as cell cycle (G2/M damage) were the top cellular functions affected ... With flow cytometry, ZINC253504760 induced G2/M phase arrest. Interestingly, ZINC253504760 induced a novel state ... activation, which induced G2/M phase arrest. ...

Abstract	Overcoming multidrug resistance (MDR) represents a major obstacle in cancer chemotherapy. Cardiac glycosides (CGs) are efficient in the treatment of heart failure and recently emerged in a new role in the treatment of cancer. ZINC253504760, a synthetic cardenolide that is structurally similar to well-known GCs, digitoxin and digoxin, has not been investigated yet. This study aims to investigate the cytotoxicity of ZINC253504760 on MDR cell lines and its molecular mode of action for cancer treatment. Four drug-resistant cell lines (P-glycoprotein-, ABCB5-, and EGFR-overexpressing cells, and TP53-knockout cells) did not show cross-resistance to ZINC253504760 except BCRP-overexpressing cells. Transcriptomic profiling indicated that cell death and survival as well as cell cycle (G2/M damage) were the top cellular functions affected by ZINC253504760 in CCRF-CEM cells, while CDK1 was linked with the downregulation of MEK and ERK. With flow cytometry, ZINC253504760 induced G2/M phase arrest. Interestingly, ZINC253504760 induced a novel state-of-the-art mode of cell death (parthanatos) through PARP and PAR overexpression as shown by western blotting, apoptosis-inducing factor (AIF) translocation by immunofluorescence, DNA damage by comet assay, and mitochondrial membrane potential collapse by flow cytometry. These results were ROS-independent. Furthermore, ZINC253504760 is an ATP-competitive MEK inhibitor evidenced by its interaction with the MEK phosphorylation site as shown by molecular docking in silico and binding to recombinant MEK by microscale thermophoresis in vitro. To the best of our knowledge, this is the first time to describe a cardenolide that induces parthanatos in leukemia cells, which may help to improve efforts to overcome drug resistance in cancer. A cardiac glycoside compound ZINC253504760 displayed cytotoxicity against different multidrug-resistant cell lines. ZINC253504760 exhibited cytotoxicity in CCRF-CEM leukemia cells by predominantly inducing a new mode of cell death (parthanatos). ZINC253504760 downregulated MEK1/2 phosphorylation and further affected ERK activation, which induced G2/M phase arrest.
MeSH term(s)	Humans ; Apoptosis ; Phosphorylation ; Cell Line, Tumor ; Cardiac Glycosides/pharmacology ; Cardiac Glycosides/therapeutic use ; Down-Regulation ; Molecular Docking Simulation ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Parthanatos ; G2 Phase Cell Cycle Checkpoints ; Neoplasm Proteins ; Leukemia/drug therapy ; Cardenolides/therapeutic use ; Mitogen-Activated Protein Kinase Kinases/therapeutic use ; Drug Resistance, Neoplasm
Chemical Substances	Cardiac Glycosides ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins ; Cardenolides ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
Language	English
Publishing date	2023-06-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	48824-0
ISSN	1573-6822 ; 0742-2091
ISSN (online)	1573-6822
ISSN	0742-2091
DOI	10.1007/s10565-023-09813-w
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Article ; Online: Modes of Action of a Novel c-MYC Inhibiting 1,2,4-Oxadiazole Derivative in Leukemia and Breast Cancer Cells.

Zhou, Min / Boulos, Joelle C / Omer, Ejlal A / Klauck, Sabine M / Efferth, Thomas

Molecules (Basel, Switzerland)

2023 Volume 28, Issue 15

Abstract: ... ...

Abstract	The
MeSH term(s)	Humans ; Female ; Plant Extracts/chemistry ; Cell Line, Tumor ; Breast Neoplasms/drug therapy ; Molecular Docking Simulation ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Antineoplastic Agents, Phytogenic/pharmacology ; Drug Resistance, Neoplasm ; Neoplasm Proteins ; Apoptosis ; Leukemia/drug therapy ; Transcriptional Elongation Factors
Chemical Substances	Plant Extracts ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Antineoplastic Agents, Phytogenic ; Neoplasm Proteins ; ELL2 protein, human ; Transcriptional Elongation Factors
Language	English
Publishing date	2023-07-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules28155658
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Article: Modulation of Intestinal Corticotropin-Releasing Hormone Signaling by the Herbal Preparation STW 5-II: Possible Mechanisms for Irritable Bowel Syndrome Management.

Elbadawi, Mohamed / Ammar, Ramy M / Rabini, Sabine / Klauck, Sabine M / Efferth, Thomas

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 9

Abstract: Corticotropin-releasing factor (CRF) mediates stress responses and alters the gut-brain axis, contributing to the pathogenesis of irritable bowel syndrome (IBS), which is recognized by abdominal pain accompanied by bowel habit disturbance. STW 5-II, a ... ...

Abstract	Corticotropin-releasing factor (CRF) mediates stress responses and alters the gut-brain axis, contributing to the pathogenesis of irritable bowel syndrome (IBS), which is recognized by abdominal pain accompanied by bowel habit disturbance. STW 5-II, a mixture of six herbal extracts, is clinically effective in functional dyspepsia and IBS. Here we aimed to establish an organoid-based stress-induced IBS-like model to investigate the mechanisms of action of STW 5-II. STW 5-II (10, 20, and 30 g/mL) was applied to intestinal organoids for 24 h before being treated with CRF (100 nM) for 48 h. The effects of STW 5-II on CRF signaling were investigated using several in vitro and in silico approaches. STW 5-II activities were further explored by in silico PyRx screening followed by molecular docking of the main 52 identified compounds in STW 5-II with both CRF receptors CRFR1 and CRFR2. CRF exposure stimulated inflammation and increased proinflammatory mediators, while STW 5-II dose-dependently counteracted these effects. STW 5-II inhibited CRF-induced claudin-2 overexpression and serotonin release. Docking of the STW 5-II constituents oleanolic acid and licorice saponin G2 to CRFR1 and CRFR2, respectively, showed a good affinity. These multi-target activities support and elucidate the clinically proven efficacy of STW 5-II in disorders of gut-brain interaction.
Language	English
Publishing date	2022-09-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15091121
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Article ; Online: Cynaropicrin disrupts tubulin and c-Myc-related signaling and induces parthanatos-type cell death in multiple myeloma.

Boulos, Joelle C / Omer, Ejlal A / Rigano, Daniela / Formisano, Carmen / Chatterjee, Manik / Leich, Ellen / Klauck, Sabine M / Shan, Le-Tian / Efferth, Thomas

Acta pharmacologica Sinica

2023 Volume 44, Issue 11, Page(s) 2265–2281

Abstract: The majority of blood malignancies is incurable and has unforeseeable remitting-relapsing paths in response to different treatments. Cynaropicrin, a natural sesquiterpene lactone from the edible parts of the artichoke plant, has gained increased ... ...

Abstract	The majority of blood malignancies is incurable and has unforeseeable remitting-relapsing paths in response to different treatments. Cynaropicrin, a natural sesquiterpene lactone from the edible parts of the artichoke plant, has gained increased attention as a chemotherapeutic agent. In this study, we investigated the effects of cynaropicrin against multiple myeloma (MM) cells in vitro and assessed its in vivo effectiveness in a xenograft tumor zebrafish model. We showed that cynaropicrin exerted potent cytotoxicity against a panel of nine MM cell lines and two leukemia cell lines with AMO1 being the most sensitive cell line (IC
MeSH term(s)	Animals ; Humans ; Tubulin ; Zebrafish/metabolism ; Multiple Myeloma/drug therapy ; Parthanatos ; Lactones/pharmacology ; Lactones/therapeutic use ; Sesquiterpenes/pharmacology ; Sesquiterpenes/therapeutic use ; Cell Line, Tumor
Chemical Substances	Tubulin ; cynaropicrin (M9233789I9) ; Lactones ; Sesquiterpenes
Language	English
Publishing date	2023-06-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	1360774-1
ISSN	1745-7254 ; 0253-9756 ; 1671-4083
ISSN (online)	1745-7254
ISSN	0253-9756 ; 1671-4083
DOI	10.1038/s41401-023-01117-3
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Article: The Novel Artemisinin Dimer Isoniazide ELI-XXIII-98-2 Induces c-MYC Inhibition, DNA Damage, and Autophagy in Leukemia Cells.

Elbadawi, Mohamed / Boulos, Joelle C / Dawood, Mona / Zhou, Min / Gul, Waseem / ElSohly, Mahmoud A / Klauck, Sabine M / Efferth, Thomas

Pharmaceutics

2023 Volume 15, Issue 4

Abstract: The proto-oncogenic transcription factor c-MYC plays a pivotal role in the development of tumorigenesis, cellular proliferation, and the control of cell death. Its expression is frequently altered in many cancer types, including hematological ... ...

Abstract	The proto-oncogenic transcription factor c-MYC plays a pivotal role in the development of tumorigenesis, cellular proliferation, and the control of cell death. Its expression is frequently altered in many cancer types, including hematological malignancies such as leukemia. The dimer isoniazide ELI-XXIII-98-2 is a derivative of the natural product artemisinin, with two artemisinin molecules and an isoniazide moiety as a linker in between them. In this study, we aimed to study the anticancer activity and the molecular mechanisms of this dimer molecule in drug-sensitive CCRF-CEM leukemia cells and their corresponding multidrug-resistant CEM/ADR5000 sub-line. The growth inhibitory activity was studied using the resazurin assay. To reveal the molecular mechanisms underlying the growth inhibitory activity, we performed in silico molecular docking, followed by several in vitro approaches such as the MYC reporter assay, microscale thermophoresis, microarray analyses, immunoblotting, qPCR, and comet assay. The artemisinin dimer isoniazide showed a potent growth inhibitory activity in CCRF-CEM but a 12-fold cross-resistance in multidrug-resistant CEM/ADR5000 cells. The molecular docking of artemisinin dimer isoniazide with c-MYC revealed a good binding (lowest binding energy of -9.84 ± 0.3 kcal/mol) and a predicted inhibition constant (pKi) of 66.46 ± 29.5 nM, which was confirmed by microscale thermophoresis and MYC reporter cell assays. Furthermore, c-MYC expression was downregulated by this compound in microarray hybridization and Western blotting analyses. Finally, the artemisinin dimer isoniazide modulated the expression of autophagy markers (LC3B and p62) and the DNA damage marker pH2AX, indicating the stimulation of both autophagy and DNA damage, respectively. Additionally, DNA double-strand breaks were observed in the alkaline comet assay. DNA damage, apoptosis, and autophagy induction could be attributed to the inhibition of c-MYC by ELI-XXIII-98-2.
Language	English
Publishing date	2023-03-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15041107
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Article ; Online: Cytotoxicity of dioncophylline A and related naphthylisoquinolines in leukemia cells, mediated by NF-κB inhibition, angiogenesis suppression, G2/M cell cycle arrest, and autophagy induction.

Yücer, Rümeysa / Fayez, Shaimaa / Feineis, Doris / Klauck, Sabine M / Shan, Letian / Bringmann, Gerhard / Efferth, Thomas / Dawood, Mona

Phytomedicine : international journal of phytotherapy and phytopharmacology

2023 Volume 126, Page(s) 155267

Abstract: ... induced G2/M arrest. It also prevented NF-κB translocation from the cytoplasm to the nucleus. Tube ...

Abstract	Background: Inhibition of NF-κB activity represents a strategy to treat acute myeloid leukemia, one of the most lethal leukemia types. Naphthylisoquinolines (NIQs) are cytotoxic alkaloids from lianas of the families Ancistrocladaceae and Dioncophyllaceae, which are indigenous to tropical rainforests. Purpose: Uncovering therapeutic possibilities and underlying molecular mechanisms of dioncophylline A and its derivatives towards NF-κB related cellular processes. Methods: Resazurin-based cell viability assay was performed for dioncophylline A and three derivatives on wild-type CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. Transcriptome analysis was executed to discover cellular functions and molecular networks associated with dioncophylline A treatment. Expression changes obtained by mRNA microarray hybridization were confirmed using qRT-PCR. Molecular docking was applied to predict the affinity of the NIQs with NF-κB. To validate the in silico approach, NF-κB reporter assays were conducted on HEK-Blue™ Null1 cells. Cell death mechanisms and cell cycle arrest were studied using flow cytometry. The potential activity on angiogenesis was evaluated with the endothelial cell tube formation assay on HUVECs using fluorescence microscopy. Intracellular NF-κB location in HEK-Blue™ Null1 cells was visualized with immunofluorescence. Finally, the anti-tumor activity of dioncophylline A was studied by a xenograft zebrafish model in vivo. Results: Our study demonstrated that dioncophylline A and its derivatives exerted potent cytotoxicity on leukemia cells. Using Ingenuity Pathway Analysis, we identified the NF-κB network as the top network, and docking experiments predicted dioncophylline A and two of its derivatives sharing the same binding pocket with the positive control compound, triptolide. Dioncophylline A showed the best inhibitory activity in NF-κB reporter assays compared to its derivatives, caused autophagy rather than apoptosis, and induced G2/M arrest. It also prevented NF-κB translocation from the cytoplasm to the nucleus. Tube formation as an angiogenesis marker was significantly suppressed by dioncophylline A treatment. Finally, the remarkable anti-tumor activity of dioncophylline A was proven in zebrafish in vivo. Conclusion: Taken together, we report for the first time the molecular mechanism behind the cytotoxic effect of dioncophylline A on leukemia cells. Dioncophylline A showed strong cytotoxic activity, inhibited NF-κB translocation, significantly affected the NF-κB in silico and in vitro, subdued tube formation, induced autophagy, and exerted antitumor activity in vivo. Our findings enlighten both the cellular functions including the NF-κB signaling pathway and the cytotoxic mechanism affected by dioncophylline A.
MeSH term(s)	Animals ; Humans ; NF-kappa B/metabolism ; Zebrafish/metabolism ; Apoptosis ; Molecular Docking Simulation ; Angiogenesis ; G2 Phase Cell Cycle Checkpoints ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Cell Cycle Checkpoints ; Autophagy ; Leukemia ; Isoquinolines
Chemical Substances	NF-kappa B ; dioncophylline A (60142-17-8) ; Antineoplastic Agents ; Isoquinolines
Language	English
Publishing date	2023-12-08
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2023.155267
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Article ; Online: Disruption of Lipid Raft Microdomains, Regulation of CD38, TP53, and MYC Signaling, and Induction of Apoptosis by Lomitapide in Multiple Myeloma Cells.

Saeed, Mohamed E M / Boulos, Joelle C / Mücklich, Sabrina B / Leich, Ellen / Chatterjee, Manik / Klauck, Sabine M / Efferth, Thomas

Cancer genomics & proteomics

2022 Volume 19, Issue 5, Page(s) 540–555

Abstract: Background/aim: Multiple myeloma (MM) is characterized by accumulation of a malignant clone of plasma cells in the bone marrow. Curative treatments are not yet available. Therefore, we undertook a drug repurposing approach to identify possible ... ...

Abstract	Background/aim: Multiple myeloma (MM) is characterized by accumulation of a malignant clone of plasma cells in the bone marrow. Curative treatments are not yet available. Therefore, we undertook a drug repurposing approach to identify possible candidates from a chemical library of 1,230 FDA-approved drugs by virtual drug screening. As a target, we have chosen the non-receptor Bruton's tyrosine kinase (BTK) which is one of the main regulators of the MM biomarker CD38. Materials and methods: In silico virtual screening was performed by using PyRx. Flow cytometry was applied for cell cycle and apoptosis analysis. Furthermore, protein and gene expression was determined by western blotting and microarray hybridization. Lipid raft staining was observed by confocal microscopy. Results: The in silico identified lipid-lowering lomitapide presented with the strongest cytotoxicity among the top 10 drug candidates. This drug arrested the cell cycle in the G Conclusion: Lomitapide treatment led to disruption of lipid raft domains and induction of pro-apoptotic factors and might, therefore, be considered as a potential therapeutic agent in MM.
MeSH term(s)	ADP-ribosyl Cyclase 1/genetics ; ADP-ribosyl Cyclase 1/metabolism ; Apoptosis/drug effects ; Benzimidazoles/pharmacology ; Cell Line, Tumor ; Humans ; Membrane Microdomains/genetics ; Membrane Microdomains/metabolism ; Membrane Microdomains/pathology ; Multiple Myeloma/drug therapy ; Multiple Myeloma/pathology ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	BMS201038 ; Benzimidazoles ; MYC protein, human ; Proto-Oncogene Proteins c-myc ; TP53 protein, human ; Tumor Suppressor Protein p53 ; ADP-ribosyl Cyclase 1 (EC 3.2.2.6)
Language	English
Publishing date	2022-08-19
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2144517-5
ISSN	1790-6245 ; 1109-6535
ISSN (online)	1790-6245
ISSN	1109-6535
DOI	10.21873/cgp.20339
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Article ; Online: Pyrrolizidine alkaloids cause cell cycle and DNA damage repair defects as analyzed by transcriptomics in cytochrome P450 3A4-overexpressing HepG2 clone 9 cells.

Abdelfatah, Sara / Naß, Janine / Knorz, Caroline / Klauck, Sabine M / Küpper, Jan-Heiner / Efferth, Thomas

Cell biology and toxicology

2021 Volume 38, Issue 2, Page(s) 325–345

Abstract: Pyrrolizidine alkaloids (PAs) are a large group of highly toxic chemical compounds, which are found as cross-contaminants in numerous food products (e.g., honey), dietary supplements, herbal teas, and pharmaceutical herbal medicines. PA contaminations ... ...

Abstract	Pyrrolizidine alkaloids (PAs) are a large group of highly toxic chemical compounds, which are found as cross-contaminants in numerous food products (e.g., honey), dietary supplements, herbal teas, and pharmaceutical herbal medicines. PA contaminations are responsible for serious hepatotoxicity and hepatocarcinogenesis. Health authorities have to set legal limit values to guarantee the safe consumption of plant-based nutritional and medical products without harmful health. Toxicological and chemical analytical methods are conventionally applied to determine legally permitted limit values for PAs. In the present investigation, we applied a highly sensitive transcriptomic approach to investigate the effect of low concentrations of five PAs (lasiocarpine, riddelliine, lycopsamine, echimidine, and monocrotaline) on human cytochrome P450 3A4-overexpressing HepG2 clone 9 hepatocytes. The transcriptomic profiling of deregulated gene expression indicated that the PAs disrupted important signaling pathways related to cell cycle regulation and DNA damage repair in the transfected hepatocytes, which may explain the carcinogenic PA effects. As PAs affected the expression of genes that involved in cell cycle regulation, we applied flow cytometric cell cycle analyses to verify the transcriptomic data. Interestingly, PA treatment led to an arrest in the S phase of the cell cycle, and this effect was more pronounced with more toxic PAs (i.e., lasiocarpine and riddelliine) than with the less toxic monocrotaline. Using immunofluorescence, high fractions of cells were detected with chromosome congression defects upon PA treatment, indicating mitotic failure. In conclusion, the tested PAs revealed threshold concentrations, above which crucial signaling pathways were deregulated resulting in cell damage and carcinogenesis. Cell cycle arrest and DNA damage repair point to the mutagenicity of PAs. The disturbance of chromosome congression is a novel mechanism of Pas, which may also contribute to PA-mediated carcinogenesis. Transcriptomic, cell cycle, and immunofluorescence analyses should supplement the standard techniques in toxicology to unravel the biological effects of PA exposure in liver cells as the primary target during metabolization of PAs.
MeSH term(s)	Carcinogenesis ; Cell Cycle ; Clone Cells/chemistry ; DNA Damage ; Hep G2 Cells ; Humans ; Monocrotaline ; Pyrrolizidine Alkaloids/analysis ; Pyrrolizidine Alkaloids/toxicity ; Transcriptome/genetics
Chemical Substances	Pyrrolizidine Alkaloids ; Monocrotaline (73077K8HYV)
Language	English
Publishing date	2021-04-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	48824-0
ISSN	1573-6822 ; 0742-2091
ISSN (online)	1573-6822
ISSN	0742-2091
DOI	10.1007/s10565-021-09599-9
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Article ; Online: Selection of safe artemisinin derivatives using a machine learning-based cardiotoxicity platform and in vitro and in vivo validation.

Kadioglu, Onat / Klauck, Sabine M / Fleischer, Edmond / Shan, Letian / Efferth, Thomas

Archives of toxicology

2021 Volume 95, Issue 7, Page(s) 2485–2495

Abstract: The majority of drug candidates fails the approval phase due to unwanted toxicities and side effects. Establishment of an effective toxicity prediction platform is of utmost importance, to increase the efficiency of the drug discovery process. For this ... ...

Abstract	The majority of drug candidates fails the approval phase due to unwanted toxicities and side effects. Establishment of an effective toxicity prediction platform is of utmost importance, to increase the efficiency of the drug discovery process. For this purpose, we developed a toxicity prediction platform with machine-learning strategies. Cardiotoxicity prediction was performed by establishing a model with five parameters (arrhythmia, cardiac failure, heart block, hypertension, myocardial infarction) and additional toxicity predictions such as hepatotoxicity, reproductive toxicity, mutagenicity, and tumorigenicity are performed by using Data Warrior and Pro-Tox-II software. As a case study, we selected artemisinin derivatives to evaluate the platform and to provide a list of safe artemisinin derivatives. Artemisinin from Artemisia annua was described first as an anti-malarial compound and later its anticancer properties were discovered. Here, random forest feature selection algorithm was used for the establishment of cardiotoxicity models. High AUC scores above 0.830 were achieved for all five cardiotoxicity indications. Using a chemical library of 374 artemisinin derivatives as a case study, 7 compounds (deoxydihydro-artemisinin, 3-hydroxy-deoxy-dihydroartemisinin, 3-desoxy-dihydroartemisinin, dihydroartemisinin-furano acetate-d3, deoxyartemisinin, artemisinin G, artemisinin B) passed the toxicity filtering process for hepatotoxicity, mutagenicity, tumorigenicity, and reproductive toxicity in addition to cardiotoxicity. Experimental validation with the cardiomyocyte cell line AC16 supported the findings from the in silico cardiotoxicity model predictions. Transcriptomic profiling of AC16 cells upon artemisinin B treatment revealed a similar gene expression profile as that of the control compound, dexrazoxane. In vivo experiments with a Zebrafish model further substantiated the in silico and in vitro data, as only slight cardiotoxicity in picomolar range was observed. In conclusion, our machine-learning approach combined with in vitro and in vivo experimentation represents a suitable method to predict cardiotoxicity of drug candidates.
MeSH term(s)	Animals ; Artemisinins/toxicity ; Cardiotoxicity ; Machine Learning ; Software ; Zebrafish
Chemical Substances	Artemisinins
Language	English
Publishing date	2021-05-22
Publishing country	Germany
Document type	Journal Article
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-021-03058-4
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