Selective reversal of BCRP-mediated MDR by VEGFR-2 inhibitor ZM323881
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Yun-Kai Zhang1, Xiao-Yu Zhang1, Guan-Nan Zhang1
1College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Abstract:
The expression of breast cancer resistant protein (BCRP) in lung cancer is correlated with development of multidrug resistance (MDR) and therefore leads to lower response to chemotherapy. ZM323881, a previously developed selective VEGFR-2 inhibitor, was found to have inhibitory effects on BCRP-mediated MDR in this investigation. ZM323881 significantly decreased the cytotoxic doses of mitoxantrone and SN-38 in BCRP-overexpressing NCI-H460/MX20 cells. Mechanistic studies revealed that ZM323881 effected by inhibiting BCRP-mediated drug efflux, leading to intracellular accumulation of BCRP substrates. No significant alteration in the expression levels and localization pattern of BCRP was observed when BCRP-overexpressing cells were exposed to ZM323881. Stimulated bell-shaped ATPase activities were observed. Molecular docking suggested that ZM323881 binds to the modulator site of BCRP and the binding pose is stable validated by 100ns molecular dynamic simulation. Overall, our results indicated that ZM323881 reversed BCRP-related MDR by inhibiting its efflux function. These findings might be useful in developing combination chemotherapy for MDR cancer treatment.
Insights
ZM323881, a VEGFR-2 inhibitor, reverses breast cancer resistance protein (BCRP)-mediated multidrug resistance (MDR) in lung cancer. It inhibits BCRP efflux, enhancing chemotherapy effectiveness and offering potential for combination treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Breast cancer resistance protein (BCRP) expression in lung cancer correlates with multidrug resistance (MDR).
- MDR significantly reduces chemotherapy response rates in cancer patients.
Purpose of the Study:
- To investigate the inhibitory effects of ZM323881, a selective VEGFR-2 inhibitor, on BCRP-mediated MDR.
- To explore the potential of ZM323881 as a chemosensitizer for overcoming MDR in lung cancer.
Main Methods:
- In vitro studies using BCRP-overexpressing NCI-H460/MX20 cells.
- Assessment of ZM323881's effect on cytotoxic doses of mitoxantrone and SN-38.
- Mechanistic studies including drug efflux assays, BCRP expression analysis, ATPase activity assays, molecular docking, and molecular dynamics simulations.
Main Results:
- ZM323881 significantly reduced the cytotoxic doses of mitoxantrone and SN-38 in BCRP-overexpressing cells.
- ZM323881 inhibited BCRP-mediated drug efflux, leading to intracellular accumulation of BCRP substrates.
- Molecular docking and dynamics simulations confirmed stable binding of ZM323881 to the BCRP modulator site, with observed stimulated ATPase activity.
Conclusions:
- ZM323881 effectively reverses BCRP-related MDR by inhibiting its efflux function.
- ZM323881 demonstrates potential as a therapeutic agent for combination chemotherapy in MDR cancer treatment.
- These findings may contribute to improved treatment strategies for multidrug-resistant lung cancers.
