Back to Search
Start Over
Reversal of P-glycoprotein-mediated multidrug resistance by natural N-alkylated indole alkaloid derivatives in KB-ChR-8-5 drug-resistant cancer cells.
- Source :
-
Journal of biochemical and molecular toxicology [J Biochem Mol Toxicol] 2023 Sep; Vol. 37 (9), pp. e23421. Date of Electronic Publication: 2023 Jun 22. - Publication Year :
- 2023
-
Abstract
- Multidrug resistance (MDR) remains a significant challenge in cancer chemotherapy due to the overexpression of ATP-binding cassette drug-efflux transporters, namely P-glycoprotein (P-gp)/ATP-binding cassette subfamily B member 1. In this study, derivatives of N-alkylated monoterpene indole alkaloids such as N-(para-bromobenzyl) (NBBT), N-(para-methylbenzyl) (NMBT), and N-(para-methoxyphenethyl) (NMPT) moieties were investigated for the reversal of P-gp-mediated MDR in drug-resistant KB colchicine-resistant 8-5 (KB-ChR-8-5) cells. Among the three indole alkaloid derivatives, the NBBT exhibited the highest P-gp inhibitory activity in a dose-dependent manner. Further, it significantly decreased P-gp overexpression by inactivating the nuclear translocation of the nuclear factor kappa B p-50 subunit. In the cell survival assay, doxorubicin showed 6.3-fold resistance (FR) in KB-ChR-8-5 cells compared with its parental KB-3-1 cells. However, NBBT significantly reduced doxorubicin FR to 1.7, 1.3, and 0.4 and showed strong synergism with doxorubicin for all the concentrations studied in the drug-resistant cells. Furthermore, NBBT and doxorubicin combination decreased the cellular migration and showed increased apoptotic incidence by downregulating Bcl-2, then activating BAX, caspase 3, and p53. The present findings suggest that NBBT could be a lead candidate for the reversal of P-gp- mediated multidrug resistance in cancer cells.<br /> (© 2023 Wiley Periodicals LLC.)
- Subjects :
- Humans
ATP Binding Cassette Transporter, Subfamily B, Member 1
Colchicine pharmacology
Drug Resistance, Neoplasm
Drug Resistance, Multiple
ATP Binding Cassette Transporter, Subfamily B
Doxorubicin pharmacology
Doxorubicin therapeutic use
ATP-Binding Cassette Transporters
Indole Alkaloids pharmacology
Indole Alkaloids therapeutic use
Adenosine Triphosphate
Cell Line, Tumor
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Neoplasms drug therapy
Alkaloids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1099-0461
- Volume :
- 37
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of biochemical and molecular toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 37345739
- Full Text :
- https://doi.org/10.1002/jbt.23421