Synergistic Interaction of Lapatinib plus Doxorubicin or 5-Fluorouracil Accelerated Cell Death of Triple Negative Breast Cancer MDA-MB-231 Cell Line

摘要

Background: Lapatinib, one of tyrosine kinase inhibitor (TKIs), is used to treat HER1/2 amplified breast cancer diseases. Its combination with other chemotherapeutic agents was effective to diminish over-expressed-HER2 cell growth. This research aimed to assess its synergistic growth inhibition in combination with doxorubicin (DOX) or 5-fluorouracil (5-FU) on MDA-MB-231 as a model of human triple negative breast cancer (TNBC) cell line. Methods: 2.5%, 5% and 10% of lapatinib IC50 concentrations were tested in pre- and post-combinations with 10% of IC50 for DOX or 5-FU. Cytotoxic and genotoxic effects were conducted using MTT assay, apoptosis-necrosis and micronucleus (MN) tests. Results: Pre-treating MDA-MB-231 cells with DOX or 5-FU for 4h followed by lapatinib for 24h enhanced cytotoxicity (p0.05) in comparison with that pre-treated with lapatinib for the same time intervals. Both pre- and post-treated MDA-MB-231 cells with lapatinib enhanced induction of apoptosis and DNA damage. The mean percentages of apoptotic cells and binucleated cells containing micronuclei were elevated remarkably (p0.05) in cells pre-treated with DOX or 5-FU rather than that pre-treated with lapatinib. Conclusion: Synergistic interaction of lapatinib in combination with DOX or 5-FU augmented cell growth inhibition, apoptotic mode of cell death and DNA damage effectively. Additionally, the synergistic effect between chemotherapeutics and TKIs possibly will allow using lower concentrations to achieve remarkable cell death.