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Comparative analysis of cisplatin treatment in in vitro 3D lung microtissue and monolayer cell cultures

Lung cancer is the leading cause of cancer related mortality worldwide, accounting for more than one million deaths per year. In spite of several therapeutic approaches the five-year survival rate is still very disappointing. Platinum-based chemotherapy for non–small cell lung carcinoma, which accounts for 85% of lung cancer cases, still remains a standard treatment. Cisplatin is one of the widely used Pt-drugs for treatment of lung cancer patients, although it has several drawbacks including the development of chemoresistance which lead to diminished drug effectiveness and subsequently therapeutic failure. Currently, anticancer drugs are tested in animal screening systems. In order to increase the human relevance of these drugs it is necessary to improve human in vitro cell-based models. To investigate the effect of cisplatin treatment, our research group has modelled lung adenocarcinoma in vitro assembling three dimensional models of the distal human lung. The tissue was built from human lung adenocarcinoma cell line and primary human lung fibroblasts. Comparative analysis of two and three dimensional mono- and cocultures has shown drastic differences in sensitivity to the drug. Our results indicate that differences in drug responsiveness correlate with alterations in the molecular microenvironment, including inflammatory cytokines and drug transporters. Apoptotic response to cisplatin was significantly higher in monolayer cell cultures compared to in vitro 3D lung micro tissues. As drug sensitivity showed marked differences, it is extremely important to carry on studies in 3D tissue environment to understand mechanisms of actions and monitor drug toxicity and drug efficacy.

lung cancer; 3D cocultures; cisplatin; drug testing

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