Overcoming Cancer Cell Drug Resistance by a Folic Acid Targeted Polymeric Conjugate of Buthionine Sulfoximine.
A549 Cells
Antimetabolites, Antineoplastic
/ chemistry
Buthionine Sulfoximine
/ chemistry
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Deoxycytidine
/ analogs & derivatives
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
/ drug effects
Drug Screening Assays, Antitumor
Folate Receptors, GPI-Anchored
/ antagonists & inhibitors
Folic Acid
/ chemistry
HeLa Cells
Humans
Molecular Structure
Polyethylene Glycols
/ chemistry
Structure-Activity Relationship
Tumor Cells, Cultured
Gemcitabine
Drug delivery
PEGylation
anti-cancer
buthionine sulfoximine
gemcitabine
glutathione
macromolecular pro-drug
pro-oxidant therapy.
Journal
Anti-cancer agents in medicinal chemistry
ISSN: 1875-5992
Titre abrégé: Anticancer Agents Med Chem
Pays: Netherlands
ID NLM: 101265649
Informations de publication
Date de publication:
2019
2019
Historique:
received:
08
01
2019
revised:
04
04
2019
accepted:
11
05
2019
pubmed:
27
6
2019
medline:
1
4
2020
entrez:
27
6
2019
Statut:
ppublish
Résumé
Glutathione (GSH), which is the predominant low molecular weight intracellular thiol in mammals, has multiple functions, such as those of protecting against oxidative stress and detoxifying endogenous and exogenous electrophiles. High GSH levels, which have been observed in various types of tumors, have been thought to contribute to the resistance of neoplastic cells to apoptotic stimuli triggered by pro-oxidant therapy. Although L-(S,R)-Buthionine Sulfoximine (BSO), a selective irreversible inhibitor of glutamate cysteine ligase, depletes GSH To demonstrate that a folate-targeted PEGylated BSO conjugate can sensitize cancer cells to a Reactive Oxygen Species (ROS)-generating anticancer agent by depleting GSH. A novel folate-targeted PEGylated-BSO conjugate was synthesized and tested in combination with gemcitabine in human cell lines that over-express (HeLa) or do not express (A549) the folate receptor. The prepared folate-PEG-GFLG-BSO conjugate proved to be efficacious in reducing GSH levels and, when used in combination with the pro-oxidant drug gemcitabine, it enhanced drug activity in the cell line overexpressing the folate receptor. The folate-PEG-GFLG-BSO conjugate studied was found to be effective in sensitizing folatereceptor positive cancer cells to the ROS-generating drug gemcitabine.
Sections du résumé
BACKGROUND
Glutathione (GSH), which is the predominant low molecular weight intracellular thiol in mammals, has multiple functions, such as those of protecting against oxidative stress and detoxifying endogenous and exogenous electrophiles. High GSH levels, which have been observed in various types of tumors, have been thought to contribute to the resistance of neoplastic cells to apoptotic stimuli triggered by pro-oxidant therapy. Although L-(S,R)-Buthionine Sulfoximine (BSO), a selective irreversible inhibitor of glutamate cysteine ligase, depletes GSH
OBJECTIVE
To demonstrate that a folate-targeted PEGylated BSO conjugate can sensitize cancer cells to a Reactive Oxygen Species (ROS)-generating anticancer agent by depleting GSH.
METHODS
A novel folate-targeted PEGylated-BSO conjugate was synthesized and tested in combination with gemcitabine in human cell lines that over-express (HeLa) or do not express (A549) the folate receptor.
RESULTS
The prepared folate-PEG-GFLG-BSO conjugate proved to be efficacious in reducing GSH levels and, when used in combination with the pro-oxidant drug gemcitabine, it enhanced drug activity in the cell line overexpressing the folate receptor.
CONCLUSION
The folate-PEG-GFLG-BSO conjugate studied was found to be effective in sensitizing folatereceptor positive cancer cells to the ROS-generating drug gemcitabine.
Identifiants
pubmed: 31241440
pii: ACAMC-EPUB-99223
doi: 10.2174/1871520619666190626114641
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Folate Receptors, GPI-Anchored
0
Deoxycytidine
0W860991D6
Polyethylene Glycols
3WJQ0SDW1A
Buthionine Sulfoximine
5072-26-4
Folic Acid
935E97BOY8
Gemcitabine
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1513-1522Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.