Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer.

Isabelle Dufau 1, * Céline Frongia 2 Flavie Sicard 3 Laure Dedieu 1 Pierre Cordelier 3 Frédéric Ausseil 1 Bernard Ducommun 2, 4 Annie Valette 2
* Auteur correspondant
1 ETaC - Pharmacochimie de la Régulation Epigénétique du Cancer
2 ITAV - Institut des Technologies Avancées en sciences du Vivant
3 CRCT - Centre de Recherche en Cancérologie de Toulouse
4 Centre Hospitalier Universitaire de Toulouse
Abstract : UNLABELLED: ABSTRACT: BACKGROUND: The multicellular tumor spheroid (MCTS) is an in vitro model associating malignant-cell microenvironment and 3D organization as currently observed in avascular tumors. METHODS: In order to evaluate the relevance of this model for pre-clinical studies of drug combinations, we analyzed the effect of gemcitabine alone and in combination with the CHIR-124 CHK1 inhibitor in a Capan-2 pancreatic cell MCTS model. RESULTS: Compared to monolayer cultures, Capan-2 MCTS exhibited resistance to gemcitabine cytotoxic effect. This resistance was amplified in EGF-deprived quiescent spheroid suggesting that quiescent cells are playing a role in gemcitabine multicellular resistance. After a prolonged incubation with gemcitabine, DNA damages and massive apoptosis were observed throughout the spheroid while cell cycle arrest was restricted to the outer cell layer, indicating that gemcitabine-induced apoptosis is directly correlated to DNA damages. The combination of gemcitabine and CHIR-124 in this MCTS model, enhanced the sensitivity to the gemcitabine antiproliferative effect in correlation with an increase in DNA damage and apoptosis. CONCLUSIONS: These results demonstrate that our pancreatic MCTS model, suitable for both screening and imaging analysis, is a valuable advanced tool for evaluating the spatio-temporal effect of drugs and drug combinations in a chemoresistant and microenvironment-depending tumor model.
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BMC Cancer, BioMed Central, 2012, 12 (1), pp.15. 〈10.1186/1471-2407-12-15〉
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Isabelle Dufau, Céline Frongia, Flavie Sicard, Laure Dedieu, Pierre Cordelier, et al.. Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer.. BMC Cancer, BioMed Central, 2012, 12 (1), pp.15. 〈10.1186/1471-2407-12-15〉. 〈inserm-00670715〉

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