In silico and in vitro studies on the anti-cancer activity of andrographolide targeting survivin in human breast cancer stem cells.
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Breast Neoplasms
/ drug therapy
Caspase 3
/ metabolism
Caspase 9
/ metabolism
Cell Line, Tumor
Diterpenes
/ pharmacology
Humans
Mesenchymal Stem Cells
/ drug effects
Molecular Docking Simulation
Neoplastic Stem Cells
/ drug effects
Survivin
/ metabolism
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
11
02
2020
accepted:
17
09
2020
entrez:
19
11
2020
pubmed:
20
11
2020
medline:
8
1
2021
Statut:
epublish
Résumé
Breast cancer stem cells (BCSCs) express high levels of the anti-apoptotic protein, survivin. This study aimed to discover a natural active compound with anti-cancer properties that targeted survivin in human breast cancer stem cells. From the seven examined compounds, andrographolide was selected as a lead compound through in silico molecular docking with survivin, caspase-9, and caspase-3. We found that the affinity between andrographolide and survivin is higher than that with caspase-9 and caspase-3. Human CD24-/CD44+ BCSCs were treated with andrographolide in vitro for 24 hours. The cytotoxic effect of andrographolide on BCSCs was compared to that on human mesenchymal stem cells (MSCs). The expression of survivin, caspase-9, and caspase-3 mRNA was analyzed using qRT-PCR, while Thr34-phosphorylated survivin and total survivin levels were determined using ELISA and Immunoblotting assay. Annexin-V/PI flow cytometry assays were performed to evaluate the apoptotic activity of andrographolide. Our results demonstrate that the CC50 of andrographolide in BCSCs was 0.32mM, whereas there was no cytotoxic effect in MSCs. Moreover, andrographolide decreased survivin and Thr34-phosphorylated survivin, thus inhibiting survivin activation and increasing survivin mRNA in BCSCs. The apoptotic activity of andrographolide was revealed by the increase of caspase-3 mRNA and protein, as well as the increase in both the early and late phases of apoptosis. In conclusion, andrographolide can be considered an anti-cancer compound that targets BCSCs due to its molecular interactions with survivin, caspase-9, and caspase-3, which induce apoptosis. We suggest that the binding of andrographolide to survivin is a critical aspect of the effect of andrographolide.
Identifiants
pubmed: 33211707
doi: 10.1371/journal.pone.0240020
pii: PONE-D-20-03995
pmc: PMC7676700
doi:
Substances chimiques
Antineoplastic Agents
0
Diterpenes
0
Survivin
0
andrographolide
410105JHGR
CASP3 protein, human
EC 3.4.22.-
CASP9 protein, human
EC 3.4.22.-
Caspase 3
EC 3.4.22.-
Caspase 9
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0240020Commentaires et corrections
Type : ErratumIn
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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