Some 2-[4-(1H-benzimidazol-1-yl) phenyl]-1H-benzimidazole derivatives overcome imatinib resistance by induction of apoptosis and reduction of P-glycoprotein activity.
Humans
Imatinib Mesylate
/ pharmacology
Molecular Docking Simulation
Drug Resistance, Neoplasm
K562 Cells
Antineoplastic Agents
/ pharmacology
Apoptosis
Fusion Proteins, bcr-abl
/ genetics
Protein Kinase Inhibitors
/ pharmacology
Benzimidazoles
/ pharmacology
ATP Binding Cassette Transporter, Subfamily B
benzimidazole
chronic myeloid leukemia
drug resistance
imatinib
Journal
Chemical biology & drug design
ISSN: 1747-0285
Titre abrégé: Chem Biol Drug Des
Pays: England
ID NLM: 101262549
Informations de publication
Date de publication:
12 2023
12 2023
Historique:
revised:
11
08
2023
received:
30
04
2023
accepted:
24
08
2023
medline:
9
11
2023
pubmed:
19
9
2023
entrez:
18
9
2023
Statut:
ppublish
Résumé
Imatinib (IMA) is a tyrosine kinase inhibitor (TKI) introduced for the chronic myeloid leukemia (CML) therapy. Emergence of IMA resistance leads to the relapse and failure in CML therapy. Benzimidazole is a heterocyclic organic compound which is widely investigated for the development of anticancer drugs. In this study, we aimed to explore the anticancer effects of some 2-[4-(1H-benzimidazol-1-yl) phenyl]-1H-benzimidazole derivatives on K562S (IMA-sensitive) and K562R (IMA-resistant) cells. To analyze the cytotoxic and apoptotic effects of the compounds, K562S, K562R, and L929 cells were exposed to increasing concentrations of the derivatives. Cytotoxic effects of compounds on cell viability were analyzed with MTT assay. Apoptosis induction, caspase3/7 activity were investigated with flow cytometry and BAX, BIM, and BAD genes expression levels were analyzed with qRT-PCR. Rhodamine123 (Rho-123) staining assays were carried out to evaluate the effect of compounds on P-glycoprotein (P-gp) activity. The hit compounds were screened using molecular docking, and the binding preference of each compounds to BCR-ABL protein was evaluated. Our results indicated that compounds triggered cytotoxicity, caspase3/7 activation in K562S and K562R cells. Rho-123 staining showed that compounds inhibited P-gp activity in K562R cells. Overall, our results reveal some benzimidazole derivatives as potential anticancer agents to overcome IMA resistance in CML.
Substances chimiques
Imatinib Mesylate
8A1O1M485B
Antineoplastic Agents
0
Fusion Proteins, bcr-abl
EC 2.7.10.2
Protein Kinase Inhibitors
0
Benzimidazoles
0
ATP Binding Cassette Transporter, Subfamily B
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1521-1533Informations de copyright
© 2023 John Wiley & Sons Ltd.
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