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Expression and function of drug transporters in 3D human lung tissue model

Lung cancers are the most common and are amongst the deadliest malignant diseases worldwide. While the various subtypes have different molecular and clinical characteristics, they still frequently share similar treatment approaches. The similarity in treatment stems from the fact that the majority of patients are presented at advanced or even metastatic stage of the disease where surgical resection is not an option. Additionally, specific biological therapies are only applicable in a small fraction of cases therefore combination chemotherapy is frequently used in an attempt to prolong survival and to slow down inevitable disease progression. Unfortunately, pre-existing or acquired multidrug resistance makes chemotherapy ineffective. Multidrug resistance (MDR) often originates from activation of drug transporters that pump out chemotherapeutic drugs from cells. Drug transporter compositions are tissue microenvironment-dependent making the expression and functional analysis of transporters extremely difficult. In our study mRNA, protein levels and functional analysis of four drug transporters, namely, ABCB1, ABCG2 SLC22A3 and SLCO4C1 were tested in human non-small cell lung cancer (NSCLC) subtypes, adenocarcinoma and squamous cell lung carcinoma cell lines. The effect of microenvironmental stimuli on drug transporter expression and function, 2 and 3 dimensional co-cultures were set up using primary human lung cell types including epithelial, endothelial and fibroblast cells. Significant differences have been identified in drug transporter expression between adenocarcinoma and squamous cell carcinoma cell lines as well as primary NSCLC subtypes. Additionally, traditional 2D monocultures of primary human lung cell types expressed drug transporters at very low levels that did not change significantly even in 3D co-cultures when the aggregates consisted only of epithelial cells and fibroblasts. However, incorporation of endothelial cells into the aggregates triggered a drastic change in the drug transporter expression pattern making it greatly similar to the drug transporter pattern of the primary healthy human lung. Modeling the human lung in vitro using a 3D co-culture aggregate is not only a proper tool for analyzing drug transporter expression, but combining the carefully selected tissue model with MultiDrugQuant Kit (by Solvo Biotechnology) makes the setup suitable for analysis of drug transporter function at similar to in vivo conditions. Based on the above results new therapeutic agents can be tested more reliably in our newly developed in vitro model system.

drug transporters; lungcancer; multidrug resistance; 3D model

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