Abstract
The objective of this study was to investigate in vitro the interactions between novel epidermal growth factor receptor kinase inhibitors (EGFRIs) developed for positron emission tomography (PET) imaging and the major efflux transporter breast cancer resistance protein (BCRP/ABCG2). Seven compounds were evaluated, using the ATPase activity assays and Madin-Darbey canine kidney (MDCK) cells overexpressing BCRP. Five of the tested compounds activated BCRP ATPase to various extent. Overexpression of BCRP conferred resistance to ML04, ML06, methoxy-Br-ML03, and PEG6-ML05 (IC50 values for inhibition of control cell proliferation 2.1 ± 0.6, 2.2 ± 0.7, 1.8 ± 1.2, and 2.8 ± 3.1 μM, respectively, compared to >50 μM in MDCK-BCRP cells). At submicromolar concentrations, none of the EGFRIs significantly inhibited BCRP. Immunoblotting studies indicated that BCRP expression is evident in cell lines utilized for in vivo tumor grafting in small animal PET imaging studies. Thus, the intensity of EGFRIs radioactivity signals previously observed in tumor xenografts reflects an interplay between transporter-mediated distribution of the probe into tumor cells and target binding. Concomitant use of efflux transporter inhibitors may help distinguish between the contribution of efflux transport and EGFR binding to the tissue signal.
Highlights
Receptor tyrosine kinases play a key role in vital cellular functions, such as cell growth, differentiation, proliferation, and survival
We evaluated in vitro the interactions of seven Madin-Darbey canine kidney vector (MDCK-pcDNA3) and novel epidermal growth factor receptor kinase inhibitor (EGFRI) developed as positron emission tomography (PET) bioprobes with breast cancer resistance protein (BCRP), in MDCK-BCRP cells were grown in Eagle’s minimum essential order to better understand the factors that affect their biodis- medium (MEM) supplemented with 10% fetal bovine serum, tribution
This study evaluated the interaction of several novel epidermal growth factor receptor (EGFR) probes with BCRP, an adenosine triphosphate binding cassette (ABC) transporter that has been previously implicated in EGFRIs efflux (Ni et al, 2010)
Summary
Receptor tyrosine kinases play a key role in vital cellular functions, such as cell growth, differentiation, proliferation, and survival. Inhibition of hyperactive tyrosine kinase signaling pathways has emerged as a promising strategy for the treatment of cancer, and several TKIs have been approved by the FDA (Levitzki and Mishani, 2006; Mishani and Hagooly, 2009; Poot et al, 2013). The most established cause of secondary resistance is the occurrence of mutations in the catalytic domain of the kinase, which restrict the binding of currently available TKIs (Levitzki and Mishani, 2006). Primary or secondary resistance may result from insufficient intracellular drug concentrations, due to poor uptake (Wang et al, 2008; Engler et al, 2011; Mandery et al, 2012) or active efflux transport (OzvegyLaczka et al, 2005; Eadie et al, 2014). Two prominent transporters involved in drug efflux from cells are P-gp
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