Abstract
Multidrug resistance (MDR) is the leading cause of treatment failure in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2, play a key role in mediating MDR by pumping anticancer drugs out from cancer cells. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) currently in phase III clinical trial for the treatment of non-small cell lung cancer. Here, we found that ceritinib remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo. Ceritinib significantly increased the intracellular accumulation of chemotherapeutic agents such as doxorubicin (DOX) by inhibiting ABCB1 or ABCG2-mediated drug efflux in the transporters-overexpressing cells. Mechanistically, ceritinib is likely a competitive inhibitor of ABCB1 and ABCG2 because it competed with [(125)I]-iodoarylazidoprazosin for photo affinity labeling of the transporters. On the other hand, at the transporters-inhibiting concentrations, ceritinib did not alter the expression level of ABCB1 and ABCG2, and phosphorylation status of AKT and ERK1/2. Thus the findings advocate further clinical investigation of combination chemotherapy of ceritinib and other conventional chemotherapeutic drugs in chemo-refractory cancer patients.
Keywords:
ABCB1; ABCG2; ATP-binding cassette transporters; ceritinib; multidrug resistance.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
-
ATP Binding Cassette Transporter, Subfamily B / genetics
-
ATP Binding Cassette Transporter, Subfamily B / metabolism
-
ATP Binding Cassette Transporter, Subfamily G, Member 2
-
ATP-Binding Cassette Transporters / antagonists & inhibitors*
-
ATP-Binding Cassette Transporters / genetics
-
ATP-Binding Cassette Transporters / metabolism
-
Anaplastic Lymphoma Kinase
-
Animals
-
Antineoplastic Agents / metabolism
-
Antineoplastic Agents / pharmacology*
-
Cell Proliferation / drug effects
-
Cell Survival / drug effects
-
Dose-Response Relationship, Drug
-
Doxorubicin / metabolism
-
Doxorubicin / pharmacology
-
Drug Resistance, Neoplasm / drug effects*
-
Drug Resistance, Neoplasm / genetics
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Gene Expression Regulation, Neoplastic
-
HEK293 Cells
-
Humans
-
Inhibitory Concentration 50
-
MCF-7 Cells
-
Mice, Nude
-
Neoplasm Proteins / antagonists & inhibitors*
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism
-
Neoplasms / drug therapy*
-
Neoplasms / genetics
-
Neoplasms / metabolism
-
Neoplasms / pathology
-
Paclitaxel / metabolism
-
Paclitaxel / pharmacology
-
Phosphorylation
-
Protein Kinase Inhibitors / pharmacology*
-
Proto-Oncogene Proteins c-akt / metabolism
-
Pyrimidines / pharmacology*
-
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
-
Receptor Protein-Tyrosine Kinases / metabolism
-
Sulfones / pharmacology*
-
Time Factors
-
Transfection
-
Tumor Burden / drug effects
-
Up-Regulation
-
Xenograft Model Antitumor Assays
Substances
-
ABCB1 protein, human
-
ABCG2 protein, human
-
ATP Binding Cassette Transporter, Subfamily B
-
ATP Binding Cassette Transporter, Subfamily G, Member 2
-
ATP-Binding Cassette Transporters
-
Antineoplastic Agents
-
Neoplasm Proteins
-
Protein Kinase Inhibitors
-
Pyrimidines
-
Sulfones
-
Doxorubicin
-
ALK protein, human
-
Alk protein, mouse
-
Anaplastic Lymphoma Kinase
-
Receptor Protein-Tyrosine Kinases
-
Proto-Oncogene Proteins c-akt
-
Extracellular Signal-Regulated MAP Kinases
-
ceritinib
-
Paclitaxel