Modulation of P-gp expression by lapatinib.
Chemotherapy drug resistance is a major obstacle in the treatment of cancer. It can result from an increase in levels of cellular drug efflux pumps, such as P-glycoprotein (P-gp). Lapatinib, a growth factor receptor tyrosine kinase inhibitor, is currently in clinical trials for treatment of breast cancer. We examined the impact of co-incubation of chemotherapy drugs in combination with lapatinib in P-gp over-expressing drug resistant cells. Unexpectedly, lapatinib treatment, at clinically relevant concentrations, increased levels of the P-gp drug transporter in a dose- and time-responsive manner. Conversely, exposure to the epidermal growth factor (EGF), an endogenous growth factor receptor ligand, resulted in a decrease in P-gp expression. Despite the lapatinib-induced alteration in P-gp expression, use of accumulation, efflux and toxicity assays demonstrated that the induced alteration in P-gp expression by lapatinib had little direct impact on drug resistance.
Dunne
Gráinne
G
National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
Breen
Laura
L
Collins
Denis M
DM
Roche
Sandra
S
Clynes
Martin
M
O'Connor
Robert
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D004815:Epidermal Growth Factor