The Combined Treatment with Chemotherapeutic Agents and the Dualsteric Muscarinic Agonist Iper-8-Naphthalimide Affects Drug Resistance in Glioblastoma Stem Cells.
ATP-Binding Cassette Transporters
/ genetics
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Brain Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cisplatin
/ pharmacology
Doxorubicin
/ pharmacology
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Glioblastoma
/ drug therapy
Humans
Muscarinic Agonists
/ pharmacology
Naphthalimides
/ pharmacology
Neoplastic Stem Cells
/ drug effects
Receptor, Muscarinic M2
/ agonists
Signal Transduction
Temozolomide
/ pharmacology
M2 muscarinic receptor
cancer stem cells
chemotherapy
drug resistance
efflux pumps
glioblastoma
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
24 07 2021
24 07 2021
Historique:
received:
25
05
2021
revised:
12
07
2021
accepted:
20
07
2021
entrez:
27
8
2021
pubmed:
28
8
2021
medline:
17
11
2021
Statut:
epublish
Résumé
Glioblastoma multiforme (GBM) is characterized by heterogeneous cell populations. Among these, the Glioblastoma Stem Cells (GSCs) fraction shares some similarities with Neural Stem Cells. GSCs exhibit enhanced resistance to conventional chemotherapy drugs. Our previous studies demonstrated that the activation of M2 muscarinic acetylcholine receptors (mAChRs) negatively modulates GSCs proliferation and survival. The aim of the present study was to analyze the ability of the M2 dualsteric agonist Iper-8-naphthalimide (N-8-Iper) to counteract GSCs drug resistance. Chemosensitivity to M2 dualsteric agonist N-8-Iper and chemotherapy drugs such as temozolomide, doxorubicin, or cisplatin was evaluated in vitro by MTT assay in two different GSC lines. Drug efflux pumps expression was evaluated by RT-PCR and qRT-PCR. By using sub-toxic concentrations of N-8-Iper combined with the individual chemotherapeutic agents, we found that only low doses of the M2 agonist combined with doxorubicin or cisplatin or temozolomide were significantly able to counteract cell growth in both GSC lines. Moreover, we evaluated as the exposure to high and low doses of N-8-Iper downregulated the ATP-binding cassette (ABC) drug efflux pumps expression levels. Our results revealed the ability of the investigated M2 agonist to counteract drug resistance in two GSC lines, at least partially by downregulating the ABC drug efflux pumps expression. The combined effects of low doses of conventional chemotherapy and M2 agonists may thus represent a novel promising pharmacological approach to impair the GSC-drug resistance in the GBM therapy.
Sections du résumé
BACKGROUND
Glioblastoma multiforme (GBM) is characterized by heterogeneous cell populations. Among these, the Glioblastoma Stem Cells (GSCs) fraction shares some similarities with Neural Stem Cells. GSCs exhibit enhanced resistance to conventional chemotherapy drugs. Our previous studies demonstrated that the activation of M2 muscarinic acetylcholine receptors (mAChRs) negatively modulates GSCs proliferation and survival. The aim of the present study was to analyze the ability of the M2 dualsteric agonist Iper-8-naphthalimide (N-8-Iper) to counteract GSCs drug resistance.
METHODS
Chemosensitivity to M2 dualsteric agonist N-8-Iper and chemotherapy drugs such as temozolomide, doxorubicin, or cisplatin was evaluated in vitro by MTT assay in two different GSC lines. Drug efflux pumps expression was evaluated by RT-PCR and qRT-PCR.
RESULTS
By using sub-toxic concentrations of N-8-Iper combined with the individual chemotherapeutic agents, we found that only low doses of the M2 agonist combined with doxorubicin or cisplatin or temozolomide were significantly able to counteract cell growth in both GSC lines. Moreover, we evaluated as the exposure to high and low doses of N-8-Iper downregulated the ATP-binding cassette (ABC) drug efflux pumps expression levels.
CONCLUSIONS
Our results revealed the ability of the investigated M2 agonist to counteract drug resistance in two GSC lines, at least partially by downregulating the ABC drug efflux pumps expression. The combined effects of low doses of conventional chemotherapy and M2 agonists may thus represent a novel promising pharmacological approach to impair the GSC-drug resistance in the GBM therapy.
Identifiants
pubmed: 34440646
pii: cells10081877
doi: 10.3390/cells10081877
pmc: PMC8391681
pii:
doi:
Substances chimiques
ATP-Binding Cassette Transporters
0
CHRM2 protein, human
0
Muscarinic Agonists
0
Naphthalimides
0
Receptor, Muscarinic M2
0
Doxorubicin
80168379AG
Cisplatin
Q20Q21Q62J
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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