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Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2012 Jul; Vol. 82 (1), pp. 47-58. Date of Electronic Publication: 2012 Apr 04. - Publication Year :
- 2012
-
Abstract
- Neratinib, an irreversible inhibitor of epidermal growth factor receptor and human epidermal receptor 2, is in phase III clinical trials for patients with human epidermal receptor 2-positive, locally advanced or metastatic breast cancer. The objective of this study was to explore the ability of neratinib to reverse tumor multidrug resistance attributable to overexpression of ATP-binding cassette (ABC) transporters. Our results showed that neratinib remarkably enhanced the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates. It is noteworthy that neratinib augmented the effect of chemotherapeutic agents in inhibiting the growth of ABCB1-overexpressing primary leukemia blasts and KBv200 cell xenografts in nude mice. Furthermore, neratinib increased doxorubicin accumulation in ABCB1-overexpressing cell lines and Rhodamine 123 accumulation in ABCB1-overexpressing cell lines and primary leukemia blasts. Neratinib stimulated the ATPase activity of ABCB1 at low concentrations but inhibited it at high concentrations. Likewise, neratinib inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner (IC(50) = 0.24 μM). Neither the expression of ABCB1 at the mRNA and protein levels nor the phosphorylation of Akt was affected by neratinib at reversal concentrations. Docking simulation results were consistent with the binding conformation of neratinib within the large cavity of the transmembrane region of ABCB1, which provides computational support for the cross-reactivity of tyrosine kinase inhibitors with human ABCB1. In conclusion, neratinib can reverse ABCB1-mediated multidrug resistance in vitro, ex vivo, and in vivo by inhibiting its transport function.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B
ATP-Binding Cassette Transporters metabolism
Adenosine Triphosphatases genetics
Adenosine Triphosphatases metabolism
Animals
Antineoplastic Agents pharmacology
Cell Line, Tumor
Doxorubicin pharmacology
Drug Resistance, Multiple drug effects
Drug Resistance, Multiple genetics
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
HEK293 Cells
HL-60 Cells
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Oncogene Protein v-akt genetics
Oncogene Protein v-akt metabolism
Phosphorylation drug effects
RNA, Messenger genetics
Rhodamines pharmacology
rho-Associated Kinases genetics
rho-Associated Kinases metabolism
ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
ATP-Binding Cassette Transporters genetics
Quinolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0111
- Volume :
- 82
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 22491935
- Full Text :
- https://doi.org/10.1124/mol.111.076299