Cytotoxicity and antimitotic activity of Rhinella schneideri and Rhinella marina venoms

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000481723600035&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.jep.2019.112049
eISSN
1872-7573
Externe Identifier
  • Clarivate Analytics Document Solution ID: IR8XA
  • PubMed Identifier: 31265888
ISSN
0378-8741
Zeitschrift
JOURNAL OF ETHNOPHARMACOLOGY
Schlüsselwörter
  • Amphibian toxins
  • Cell cycle arrest
  • Leukemia
  • Microtubules
  • Molecular docking
  • Natural products
Artikelnummer
ARTN 112049
Datum der Veröffentlichung
2019
Status
Published
Titel
Cytotoxicity and antimitotic activity of <i>Rhinella</i> <i>schneideri</i> and <i>Rhinella</i> <i>marina</i> venoms
Sub types
  • Article
Ausgabe der Zeitschrift
242

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
DOI
10.1016/j.jep.2019.112049
ISSN
0378-8741
Zeitschrift
Journal of Ethnopharmacology
Sprache
en
Artikelnummer
112049
Paginierung
112049 - 112049
Datum der Veröffentlichung
2019
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.jep.2019.112049
Datum der Datenerfassung
2021
Titel
Cytotoxicity and antimitotic activity of Rhinella schneideri and Rhinella marina venoms
Ausgabe der Zeitschrift
242

Data source: Crossref

Abstract
<h4>Ethnopharmacological relevance</h4>Rhinella schneideri and Rhinella marina are toad venoms distributed in different parts of the world, including Brazil, Columbia and amazon. Venoms extracted from different species have many clinical applications such as antimicrobial cardiotonics and treatment of cancer. Aim of the study; In this study, we aim to investigate the effect of venoms extracted from R. schneideri and R. marina on cancer cells and verify possible mechanism of action.<h4>Material and method</h4>Cytotoxicity analyses was performed using the resazurin reduction assay, where different concentrations of venoms were tested against sensitive CCRF-CEM and P-gp overexpressing ADR/CEM5000 leukemia cells. Programmed cell death was investigated using the flow cytometric annexin V/propidium iodide apoptosis assay. Furthermore, we analyzed flow cytometric cell cycle analyses of CCRF-CEM cells. Effect on tubulin formation was tested using molecular docking and fluorescence microscopy of U2OS-GFP-α-tubulin osteosarcoma cells treated for 24 h with venoms.<h4>Results</h4>Cytotoxicity assays revealed a strong activity towards wild-type CCRF-CEM cells (IC<sub>50</sub> values of 0.202 ± 0.005 μg/ml and 0.18 ± 0.007 μg/ml for R. schneideri and R. marina, respectively) and multidrug-resistant CEM/ADR5000 cells (IC<sub>50</sub> 0.403 ± 0.084 μg/ml and 0.32 ± 0.077 μg/ml for R. schneideri and R. marina, respectively). The venoms induced apoptosis as major mechanism of cell death. The venoms induced strong G2/M cell arrest in CCRF-CEM cells. We suggested tubulin as a major target for the venoms. In silico molecular docking of the major constituents of the venoms, i.e. bufalin, marinobufagin, telocinbufagin, hellebrigenin, showed strong binding affinities to tubulin. This result was verified in vitro. The venoms dysregulated microtubule arrangement of U2OS cells expressing GFP-labeled tubulin. Toxicity predictions by QSAR methodology highlighted the toxic features of bufadienolides.<h4>Conclusion</h4>Our study demonstrated the importance of toad venoms as source of cytotoxic compounds that may serve as lead compounds for the development of novel anticancer drugs.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, 55128, Germany. Electronic address: saabdelf@uni-mainz.de.
Autoren
DOI
10.1016/j.jep.2019.112049
eISSN
1872-7573
Externe Identifier
  • PubMed Identifier: 31265888
Funding acknowledgements
  • Deutscher Akademischer Austauschdienst:
Open access
false
ISSN
0378-8741
Zeitschrift
Journal of ethnopharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Animals
  • Bufonidae
  • Humans
  • Tubulin
  • Amphibian Venoms
  • Lethal Dose 50
  • Cell Survival
  • Antimitotic Agents
  • Cell Cycle Checkpoints
  • Molecular Docking Simulation
Sprache
eng
Medium
Print-Electronic
Online publication date
2019
Paginierung
112049
Datum der Veröffentlichung
2019
Status
Published
Datum der Datenerfassung
2019
Titel
Cytotoxicity and antimitotic activity of Rhinella schneideri and Rhinella marina venoms.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
242

Data source: Europe PubMed Central

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Rhinella schneideri and Rhinella marina are toad venoms distributed in different parts of the world, including Brazil, Columbia and amazon. Venoms extracted from different species have many clinical applications such as antimicrobial cardiotonics and treatment of cancer. Aim of the study; In this study, we aim to investigate the effect of venoms extracted from R. schneideri and R. marina on cancer cells and verify possible mechanism of action. MATERIAL AND METHOD: Cytotoxicity analyses was performed using the resazurin reduction assay, where different concentrations of venoms were tested against sensitive CCRF-CEM and P-gp overexpressing ADR/CEM5000 leukemia cells. Programmed cell death was investigated using the flow cytometric annexin V/propidium iodide apoptosis assay. Furthermore, we analyzed flow cytometric cell cycle analyses of CCRF-CEM cells. Effect on tubulin formation was tested using molecular docking and fluorescence microscopy of U2OS-GFP-α-tubulin osteosarcoma cells treated for 24 h with venoms. RESULTS: Cytotoxicity assays revealed a strong activity towards wild-type CCRF-CEM cells (IC50 values of 0.202 ± 0.005 μg/ml and 0.18 ± 0.007 μg/ml for R. schneideri and R. marina, respectively) and multidrug-resistant CEM/ADR5000 cells (IC50 0.403 ± 0.084 μg/ml and 0.32 ± 0.077 μg/ml for R. schneideri and R. marina, respectively). The venoms induced apoptosis as major mechanism of cell death. The venoms induced strong G2/M cell arrest in CCRF-CEM cells. We suggested tubulin as a major target for the venoms. In silico molecular docking of the major constituents of the venoms, i.e. bufalin, marinobufagin, telocinbufagin, hellebrigenin, showed strong binding affinities to tubulin. This result was verified in vitro. The venoms dysregulated microtubule arrangement of U2OS cells expressing GFP-labeled tubulin. Toxicity predictions by QSAR methodology highlighted the toxic features of bufadienolides. CONCLUSION: Our study demonstrated the importance of toad venoms as source of cytotoxic compounds that may serve as lead compounds for the development of novel anticancer drugs.
Date of acceptance
2019
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/31265888
DOI
10.1016/j.jep.2019.112049
eISSN
1872-7573
Zeitschrift
J Ethnopharmacol
Schlüsselwörter
  • Amphibian toxins
  • Cell cycle arrest
  • Leukemia
  • Microtubules
  • Molecular docking
  • Natural products
  • Amphibian Venoms
  • Animals
  • Antimitotic Agents
  • Bufonidae
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Survival
  • Humans
  • Lethal Dose 50
  • Molecular Docking Simulation
  • Tubulin
Sprache
eng
Country
Ireland
Paginierung
112049
PII
S0378-8741(19)30807-4
Datum der Veröffentlichung
2019
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2020
Titel
Cytotoxicity and antimitotic activity of Rhinella schneideri and Rhinella marina venoms.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
242

Data source: PubMed

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