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Modulation of P-gp expression by lapatinib
Gráinne Dunne1, Laura Breen, Denis M Collins
1National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
Investigational New Drugs
|July 8, 2010
Summary
Lapatinib, used in breast cancer treatment, unexpectedly increased P-glycoprotein (P-gp) drug transporter levels in resistant cells. However, this did not significantly impact chemotherapy drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy drug resistance is a significant challenge in cancer therapy.
- Increased expression of drug efflux pumps, like P-glycoprotein (P-gp), contributes to this resistance.
- Lapatinib is an investigational tyrosine kinase inhibitor for breast cancer.
Purpose of the Study:
- To investigate the effect of lapatinib on P-gp expression in drug-resistant cancer cells.
- To determine if lapatinib affects chemotherapy drug resistance in P-gp over-expressing cells.
Main Methods:
- Co-incubation of P-gp over-expressing cells with chemotherapy drugs and lapatinib.
- Dose- and time-response studies of lapatinib on P-gp levels.
- Accumulation, efflux, and toxicity assays to assess drug resistance.
- Comparison with the effect of epidermal growth factor (EGF) on P-gp.
Main Results:
- Lapatinib treatment increased P-gp transporter levels in a dose- and time-dependent manner.
- Epidermal growth factor (EGF) exposure decreased P-gp expression.
- Despite increased P-gp levels, lapatinib showed minimal direct impact on overall drug resistance.
Conclusions:
- Lapatinib can upregulate P-gp expression in resistant cancer cells.
- This lapatinib-induced increase in P-gp does not significantly alter chemotherapy drug resistance.
- Further research is needed to understand the complex interactions between lapatinib and drug efflux pumps.
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