Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition.
Cancer Lett
; 453: 57-73, 2019 07 01.
Article
em En
| MEDLINE
| ID: mdl-30930233
ABSTRACT
Natural products possess a significant role in anticancer therapy and many currently-used anticancer drugs are of natural origin. Cerberin (CR), a cardenolide isolated from the fruit kernel of Cerbera odollam, was found to potently inhibit cancer cell growth (GI50 valuesâ¯<â¯90â¯nM), colony formation and migration. Significant G2/M cell cycle arrest preceded time- and dose-dependent apoptosis-induction in human cancer cell lines corroborated by dose-and time-dependent PARP cleavage and caspase 3/7 activation, in addition to reduced Bcl-2 and Mcl-1 expression. CR potently inhibited PI3K/AKT/mTOR signalling depleting polo-like kinase 1 (PLK-1), c-Myc and STAT-3 expression. Additionally, CR significantly increased the generation of reactive oxygen species (ROS) producing DNA double strand breaks. Preliminary in silico biopharmaceutical assessment of CR predicted >60% bioavailability and rapid absorption; doses of 1-10â¯mg/kg CR were predicted to maintain efficacious unbound plasma concentrations (>GI50 value). CR's potent and selective anti-tumour activity, and its targeting of key signalling mechanisms pertinent to tumourigenesis support further preclinical evaluation of this cardiac glycoside.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cardenolídeos
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Transdução de Sinais
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Proteínas Proto-Oncogênicas c-akt
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Serina-Treonina Quinases TOR
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Inibidores de Fosfoinositídeo-3 Quinase
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Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Cancer Lett
Ano de publicação:
2019
Tipo de documento:
Article