Collateral sensitivity of drug-resistant ABCB5- and mutation-activated EGFR overexpressing cells towards resveratrol due to modulation of SIRT1 expression.
ATP Binding Cassette Transporter, Subfamily B
/ genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1
/ metabolism
Antineoplastic Agents, Phytogenic
/ pharmacology
Cell Line, Tumor
Drug Resistance, Multiple
Drug Resistance, Neoplasm
/ drug effects
ErbB Receptors
/ genetics
Gene Expression Regulation, Neoplastic
Humans
Mutation
NF-kappa B
/ genetics
Promoter Regions, Genetic
Resveratrol
/ pharmacology
Sirtuin 1
/ metabolism
Cancer
Drug resistance
Microarray
Pharmacogenomics
Phytoalexin
Sirtuins
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:
Jun 2019
Jun 2019
Historique:
received:
17
12
2018
revised:
09
03
2019
accepted:
12
03
2019
pubmed:
29
3
2019
medline:
17
9
2019
entrez:
29
3
2019
Statut:
ppublish
Résumé
In the drug discovery field, natural products deemed a precious source of novel lead compounds. They have the ability to bypass or overcome multidrug resistance (MDR) in cancer cells. In this study, the natural polyphenolic stilbene resveratrol (RES) has been studied for its cytotoxic activity toward MDR cancer cells. Resazurin assay was used to investigate the cytotoxicity of RES not only against a panel of drug-resistant cancer cells overexpressing P-glycoprotein/ABCB1, BCRP/ABCG2, ABCB5 (ATP-binding cassette transporters), but also mutation-activated EGFR. The assessment of proteins expression was done by Western blot analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to RES. The NF-κB activation was evaluated using NF-kB reporter cells assay. Interestingly, MDR cells overexpressing ABCB5 and mutation-activated EGFR were collateral sensitive (CS) to RES. Our immunoblotting analysis highlighted that CS may be attributed to RES-induced sirtuin 1 (SIRT1) overexpression. Indeed, the SIRT1 inhibitor, sirtinol completely abolished CS to RES, indicating a causative role of SIRT1 for CS to RES. In addition, COMPARE and hierarchical cluster analyses of transcriptomic data indicated genes associated with diverse cellular mechanisms ranging from the immune response, inflammation signaling, and microtubule formation to cell migration. Searching for transcription factor binding motifs in the promoters of these genes pointed to NF-κB as one of the master regulators related to RES activity. The findings demonstrate that RES alone or in combination with established chemotherapeutic agents might overcome the refractory tumors. This information may be immensely useful for the development of personalized treatment.
Sections du résumé
BACKGROUND
BACKGROUND
In the drug discovery field, natural products deemed a precious source of novel lead compounds. They have the ability to bypass or overcome multidrug resistance (MDR) in cancer cells.
PURPOSE
OBJECTIVE
In this study, the natural polyphenolic stilbene resveratrol (RES) has been studied for its cytotoxic activity toward MDR cancer cells.
METHODS
METHODS
Resazurin assay was used to investigate the cytotoxicity of RES not only against a panel of drug-resistant cancer cells overexpressing P-glycoprotein/ABCB1, BCRP/ABCG2, ABCB5 (ATP-binding cassette transporters), but also mutation-activated EGFR. The assessment of proteins expression was done by Western blot analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to RES. The NF-κB activation was evaluated using NF-kB reporter cells assay.
RESULTS
RESULTS
Interestingly, MDR cells overexpressing ABCB5 and mutation-activated EGFR were collateral sensitive (CS) to RES. Our immunoblotting analysis highlighted that CS may be attributed to RES-induced sirtuin 1 (SIRT1) overexpression. Indeed, the SIRT1 inhibitor, sirtinol completely abolished CS to RES, indicating a causative role of SIRT1 for CS to RES. In addition, COMPARE and hierarchical cluster analyses of transcriptomic data indicated genes associated with diverse cellular mechanisms ranging from the immune response, inflammation signaling, and microtubule formation to cell migration. Searching for transcription factor binding motifs in the promoters of these genes pointed to NF-κB as one of the master regulators related to RES activity.
CONCLUSION
CONCLUSIONS
The findings demonstrate that RES alone or in combination with established chemotherapeutic agents might overcome the refractory tumors. This information may be immensely useful for the development of personalized treatment.
Identifiants
pubmed: 30921566
pii: S0944-7113(19)30060-1
doi: 10.1016/j.phymed.2019.152890
pii:
doi:
Substances chimiques
ABCB1 protein, human
0
ABCB5 protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
ATP Binding Cassette Transporter, Subfamily B, Member 1
0
Antineoplastic Agents, Phytogenic
0
NF-kappa B
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
SIRT1 protein, human
EC 3.5.1.-
Sirtuin 1
EC 3.5.1.-
Resveratrol
Q369O8926L
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
152890Informations de copyright
Copyright © 2019. Published by Elsevier GmbH.