Reactive Oxygen Species-Mediated Apoptosis and Cytotoxicity of Newly Synthesized Pyridazin-3-Ones In P815 (Murin Mastocytoma) Cell Line.
Animals
Antineoplastic Agents
/ administration & dosage
Apoptosis
/ drug effects
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Glutathione Reductase
/ antagonists & inhibitors
Leukocytes, Mononuclear
Lipid Peroxidation
/ drug effects
Mastocytoma
/ drug therapy
Mice
Oxidative Stress
/ drug effects
Pyridazines
/ administration & dosage
Reactive Oxygen Species
/ metabolism
Thioredoxin-Disulfide Reductase
/ antagonists & inhibitors
Journal
Drug research
ISSN: 2194-9387
Titre abrégé: Drug Res (Stuttg)
Pays: Germany
ID NLM: 101602406
Informations de publication
Date de publication:
Oct 2019
Oct 2019
Historique:
pubmed:
30
6
2019
medline:
19
2
2020
entrez:
29
6
2019
Statut:
ppublish
Résumé
In cancer cells, the intracellular antioxidant capacity and the redox homeostasis are mainly maintained by the glutathione- and thioredoxin-dependent systems which are considered as promising targets for anticancer drugs. Pyridazinones constitute an interesting source of heterocyclic compounds for drug discovery. The present investigation focused on studying the in-vitro antitumor activity of newly synthesized Pyridazin-3(2h)-ones derivatives against P815 (Murin mastocytoma) cell line. The in-vitro cytotoxic activities were investigated toward the P815 cell line using tetrazolium-based MTT assay. Lipid peroxidation and the specific activities of antioxidant enzymes were also determined. The newly compounds had a selective dose-dependent cytotoxic effect without affecting normal cells (PBMCs). Apoptosis was further confirmed through the characteristic apoptotic morphological changes and DNA fragmentation. Two compounds (6F: and 7H: ) were highly cytotoxic and were submitted to extend biological testing to determine the likely mechanisms of their cytotoxicity. Results showed that these molecules may induce cytotoxicity via disturbing the redox homeostasis. Importantly, the anticancer activity of 6F: and 7H: could be due to the intracellular reactive oxygen species hypergeneration through significant loss of glutathione reductase and thioredoxin reductase activities. This eventually leads to oxidative stress-mediated P815 cell apoptosis. Furthermore, the co-administration of 6F: or 7H: with Methotrexate exhibited a synergistic cytotoxic effect. considering their significant anticancer activity and chemosensitivity, 6F: and 7H: may improve the therapeutic efficacy of the current treatment for cancer.
Sections du résumé
BACKGROUND
BACKGROUND
In cancer cells, the intracellular antioxidant capacity and the redox homeostasis are mainly maintained by the glutathione- and thioredoxin-dependent systems which are considered as promising targets for anticancer drugs. Pyridazinones constitute an interesting source of heterocyclic compounds for drug discovery. The present investigation focused on studying the in-vitro antitumor activity of newly synthesized Pyridazin-3(2h)-ones derivatives against P815 (Murin mastocytoma) cell line.
METHODS
METHODS
The in-vitro cytotoxic activities were investigated toward the P815 cell line using tetrazolium-based MTT assay. Lipid peroxidation and the specific activities of antioxidant enzymes were also determined.
RESULTS
RESULTS
The newly compounds had a selective dose-dependent cytotoxic effect without affecting normal cells (PBMCs). Apoptosis was further confirmed through the characteristic apoptotic morphological changes and DNA fragmentation. Two compounds (6F: and 7H: ) were highly cytotoxic and were submitted to extend biological testing to determine the likely mechanisms of their cytotoxicity. Results showed that these molecules may induce cytotoxicity via disturbing the redox homeostasis. Importantly, the anticancer activity of 6F: and 7H: could be due to the intracellular reactive oxygen species hypergeneration through significant loss of glutathione reductase and thioredoxin reductase activities. This eventually leads to oxidative stress-mediated P815 cell apoptosis. Furthermore, the co-administration of 6F: or 7H: with Methotrexate exhibited a synergistic cytotoxic effect.
CONCLUSIONS
CONCLUSIONS
considering their significant anticancer activity and chemosensitivity, 6F: and 7H: may improve the therapeutic efficacy of the current treatment for cancer.
Substances chimiques
Antineoplastic Agents
0
Pyridazines
0
Reactive Oxygen Species
0
Glutathione Reductase
EC 1.8.1.7
Thioredoxin-Disulfide Reductase
EC 1.8.1.9
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
528-536Informations de copyright
© Georg Thieme Verlag KG Stuttgart · New York.
Déclaration de conflit d'intérêts
No conflict of interest has been declared by the authors.