Oxocrebanine: A Novel Dual Topoisomerase inhibitor, Suppressed the Proliferation of Breast Cancer Cells MCF-7 by Inducing DNA Damage and Mitotic Arrest.
Alkaloids
/ pharmacology
Antineoplastic Agents, Phytogenic
/ chemistry
Aporphines
/ chemistry
Breast Neoplasms
/ drug therapy
Cell Cycle
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
DNA Damage
DNA Topoisomerases, Type I
/ metabolism
DNA Topoisomerases, Type II
/ metabolism
Drug Screening Assays, Antitumor
Female
Humans
MCF-7 Cells
Mitosis
/ drug effects
Topoisomerase Inhibitors
/ chemistry
DNA damage
MCF-7 cells
Mitotic arrest
Oxocrebanine
Stephania hainanensis H. S. Lo et Y. Tsoong
Topoisomerase
Journal
Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Titre abrégé: Phytomedicine
Pays: Germany
ID NLM: 9438794
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
26
10
2020
revised:
28
01
2021
accepted:
07
02
2021
pubmed:
22
2
2021
medline:
2
6
2021
entrez:
21
2
2021
Statut:
ppublish
Résumé
DNA topoisomerase (Topo) inhibition plays key role in breast cancer treatment. Stephania hainanensis H. S. Lo et Y. Tsoong (S. hainanensis), a Li nationality plant that has abundant aporphine alkaloids, can inhibit Topo. To identify a dual Topo inhibitor, a deep and systematic study of active aporphine alkaloids in S. hainanensis and their mechanisms of inhibiting breast cancer proliferation and Topo activity are essential. This study aimed to assess the anti-breast cancer and Topo inhibitory activities of oxocrebanine and explore the underlying mechanisms. The growth inhibitory activities of 12 compounds in S. hainanensis were screened by MTT assay in MCF-7, SGC-7901, HepG-2 cells, and compared with the effects on human normal mammary epithelial MCF-10A cells as non cancer control cells. The Topo inhibitory activity was assessed by DNA relaxation and unwinding assays, kDNA decatenation assay and western blot. Cell cycle and autophagy analyses were carried out with flow cytometry and staining. Acridine orange staining and α-tubulin morphology were observed by fluorescence microscopy. Western blot was used to examine microtubule assembly dynamics and the expression levels of key proteins associated with DNA damage, autophagy and mitotic arrest. Oxocrebanine was the anti-breast cancer active alkaloid in S. hainanensis. It exhibited the best inhibitory effect on MCF-7 cells with an IC Oxocrebanine was the anti-breast cancer active aporphine alkaloid in S. hainanensis. Oxocrebanine was a Topo I/IIα dual inhibitor, catalytic inhibitor and DNA intercalator. Oxocrebanine caused DNA damage, autophagy, and mitotic arrest in MCF-7 cells. Oxocrebanine also disrupted tubulin polymerization. Accordingly, oxocrebanine held a great potential for development as a novel dual Topo inhibitor for effective breast cancer treatment.
Sections du résumé
BACKGROUND
BACKGROUND
DNA topoisomerase (Topo) inhibition plays key role in breast cancer treatment. Stephania hainanensis H. S. Lo et Y. Tsoong (S. hainanensis), a Li nationality plant that has abundant aporphine alkaloids, can inhibit Topo.
PURPOSE
OBJECTIVE
To identify a dual Topo inhibitor, a deep and systematic study of active aporphine alkaloids in S. hainanensis and their mechanisms of inhibiting breast cancer proliferation and Topo activity are essential.
STUDY DESIGN
METHODS
This study aimed to assess the anti-breast cancer and Topo inhibitory activities of oxocrebanine and explore the underlying mechanisms.
METHODS
METHODS
The growth inhibitory activities of 12 compounds in S. hainanensis were screened by MTT assay in MCF-7, SGC-7901, HepG-2 cells, and compared with the effects on human normal mammary epithelial MCF-10A cells as non cancer control cells. The Topo inhibitory activity was assessed by DNA relaxation and unwinding assays, kDNA decatenation assay and western blot. Cell cycle and autophagy analyses were carried out with flow cytometry and staining. Acridine orange staining and α-tubulin morphology were observed by fluorescence microscopy. Western blot was used to examine microtubule assembly dynamics and the expression levels of key proteins associated with DNA damage, autophagy and mitotic arrest.
RESULTS
RESULTS
Oxocrebanine was the anti-breast cancer active alkaloid in S. hainanensis. It exhibited the best inhibitory effect on MCF-7 cells with an IC
CONCLUSION
CONCLUSIONS
Oxocrebanine was the anti-breast cancer active aporphine alkaloid in S. hainanensis. Oxocrebanine was a Topo I/IIα dual inhibitor, catalytic inhibitor and DNA intercalator. Oxocrebanine caused DNA damage, autophagy, and mitotic arrest in MCF-7 cells. Oxocrebanine also disrupted tubulin polymerization. Accordingly, oxocrebanine held a great potential for development as a novel dual Topo inhibitor for effective breast cancer treatment.
Identifiants
pubmed: 33611211
pii: S0944-7113(21)00046-5
doi: 10.1016/j.phymed.2021.153504
pii:
doi:
Substances chimiques
Alkaloids
0
Antineoplastic Agents, Phytogenic
0
Aporphines
0
Topoisomerase Inhibitors
0
oxocrebanine
0
DNA Topoisomerases, Type I
EC 5.99.1.2
TOP1 protein, human
EC 5.99.1.2
DNA Topoisomerases, Type II
EC 5.99.1.3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
153504Informations de copyright
Copyright © 2021 Elsevier GmbH. All rights reserved.