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- Comparative study of the therapeutic effect of Doxorubicin and Resveratrol combination on 2D and 3D (spheroids) cell culture modelsPublication . Barros, Andreia; Costa, Elisabete C.; Nunes, Ana Raquel Santos; Diogo, Duarte Miguel de Melo; Correia, Ilídio Joaquim SobreiraThe assessment of drug-combinations for pancreatic cancer treatment is usually performed in 2D cell cultures. In this study, the therapeutic effect and the synergistic potential of a particular drug-combination towards 2D and 3D cell cultures of pancreatic cancer were compared for the first time. Thus, the effect of Doxorubicin:Resveratrol (DOX:RES) combinations (at molar ratios ranging from 5:1 to 1:5) in the viability of PANC-1 cells cultured as 2D monolayers and as 3D spheroids was analyzed. The results showed that the cells’ viability was more affected when DOX:RES combinations containing higher contents of RES (1:2–1:5 molar ratios) were used. This can be explained by the ability of RES to reduce the P-glycoprotein (P-gp)-mediated efflux of DOX. Further, it was also revealed that the synergic effect of this drug combination was different in 2D and in 3D cell cultures. In fact, despite of the 1:4 and 1:5 DOX:RES ratios being both synergistic for both types of PANC-1 cell cultures, their Combination Indexes (CI) in the monolayers were lower than those attained in spheroids. Overall, the obtained results revealed that the DOX:RES combination is promising for pancreatic cancer treatment and corroborate the emergent need to evaluate drug combinations in 3D cell cultures.
- Modelos tumorais 2D e 3D para a avaliação de fármacosPublication . Barros, Andreia Sofia de Sousa; Correia, Ilídio Joaquim Sobreira; Costa, Elisabete Cristina da RochaDrug combination emerged as a solution for the treatment of cancer, once this therapeutic approach allows to surpass the drug resistance of cancer cells and, simultaneously, eradicate the tumor. The assessment of drug-combination for pancreatic cancer treatment is usually performed in 2D cell cultures. However, these models are unable to mimic the drug resistance profiles found in pancreatic cancer. Thus, they may overestimate the therapeutic potential of the drug combination, leading to poor therapeutic performance in in vivo assays. Therefore, 3D culture models, especially spheroids, appear as a promising method for screening anticancer drugs, since they are able to mimic the structural and functional features of solid tumors. In the present study, the therapeutic effect and the synergistic potential of a particular combination of drugs in 2D and 3D cell cultures were analyzed and compared for the first time. In this way, the effect of the combination of Doxorubicin:Resveratrol (DOX:RES) (at molar ratios ranging from 5: 1 to 1: 5), in the viability of the pancreatic cancer cell line, PANC-1, was studied. The results showed that the viability of PANC-1 cells was more affected when the DOX:RES combinations contained a higher content of RES (molar ratios of 1:2 to 1:5). These results can be explained, by the ability of RES to reduce the efflux of DOX, mediated by P-glycoprotein (P-gp). Furthermore, these data also revealed that the synergistic effect of the DOX:RES combination was different in both 2D and 3D cell cultures. In fact, although 1:4 and 1:5 DOX: RES ratios were synergistic for these types of cell cultures, their values Combination Index (CI) were lower (more synergistic) in 2D cultures, when compared to spheroids. Overall, the results obtained revealed that the combination DOX:RES is promising approach for the treatment of pancreatic cancer and corroborate the need to perform drug screening.
- 3D tumor spheroids as in vitro models to mimic in vivo human solid tumors resistance to therapeutic drugsPublication . Nunes, Ana S.; Barros, Andreia; Costa, Elisabete; Moreira, André; Correia, I.J.Three-dimensional cell culture models, such as spheroids, can be used in the process of the development of new anticancer agents because they are able to closely mimic the main features of human solid tumors, namely their structural organization, cellular layered assembling, hypoxia, and nutrient gradients. These properties imprint to the spheroids an anticancer therapeutics resistance profile, which is similar to that displayed by human solid tumors. In this review, an overview of the drug resistance mechanisms observed in 3D tumor spheroids is provided. Furthermore, comparisons between the therapeutics resistance profile exhibited by spheroids, and 2D cell cultures are presented. Finally, examples of the therapeutic approaches that have been developed to surpass the drug resistance mechanisms exhibited by spheroids are described.
- Establishment of 2D Cell Cultures Derived From 3D MCF‐7 Spheroids Displaying a Doxorubicin Resistant ProfilePublication . Nunes, Ana Raquel Santos; Costa, Elisabete C.; Barros, Andreia; Diogo, Duarte Miguel de Melo; Correia, Ilídio Joaquim SobreiraIn vitro 3D cancer spheroids generally exhibit a drug resistance profile similar to that found in solid tumors. Due to this property, these models are an appealing for anticancer compounds screening. Nevertheless, the techniques and methods aimed for drug discovery are mostly standardized for cells cultured in 2D. The development of 2D cell culture models displaying a drug resistant profile is required to mimic the in vivo tumors, while the equipment, techniques, and methodologies established for conventional 2D cell cultures can continue to be employed in compound screening. In this work, the response of 3D‐derived MCF‐7 cells subsequently cultured in 2D in medium supplemented with glutathione (GSH) (antioxidant agent found in high levels in breast cancer tissues and a promoter of cancer cells resistance) to Doxorubicin (DOX) is evaluated. These cells demonstrated a resistance toward DOX closer to that displayed by 3D spheroids, which is higher than that exhibited by standard 2D cell cultures. In fact, the 50% inhibitory concentration (IC50) of DOX in 3D‐derived MCF‐7 cell cultures supplemented with GSH is about eight‐times higher than that obtained for conventional 2D cell cultures (cultured without GSH), and is only about two‐times lower than that attained for 3D MCF‐7 spheroids (cultured without GSH). Further investigation revealed that this improved resistance of 3D‐derived MCF‐7 cells may result from their increased P‐glycoprotein (P‐gp) activity and reduced production of intracellular reactive oxygen species (ROS).
- Establishment of 2D Cell Cultures Derived From 3D MCF‐7 Spheroids Displaying a Doxorubicin Resistant ProfilePublication . Nunes, Ana S.; Costa, Elisabete; Barros, Andreia; Diogo, Duarte de Melo; Correia, I.J.In vitro 3D cancer spheroids generally exhibit a drug resistance profile similar to that found in solid tumors. Due to this property, these models are an appealing for anticancer compounds screening. Nevertheless, the techniques and methods aimed for drug discovery are mostly standardized for cells cultured in 2D. The development of 2D cell culture models displaying a drug resistant profile is required to mimic the in vivo tumors, while the equipment, techniques, and methodologies established for conventional 2D cell cultures can continue to be employed in compound screening. In this work, the response of 3D-derived MCF-7 cells subsequently cultured in 2D in medium supplemented with glutathione (GSH) (antioxidant agent found in high levels in breast cancer tissues and a promoter of cancer cells resistance) to Doxorubicin (DOX) is evaluated. These cells demonstrated a resistance toward DOX closer to that displayed by 3D spheroids, which is higher than that exhibited by standard 2D cell cultures. In fact, the 50% inhibitory concentration (IC50 ) of DOX in 3D-derived MCF-7 cell cultures supplemented with GSH is about eight-times higher than that obtained for conventional 2D cell cultures (cultured without GSH), and is only about two-times lower than that attained for 3D MCF-7 spheroids (cultured without GSH). Further investigation revealed that this improved resistance of 3D-derived MCF-7 cells may result from their increased P-glycoprotein (P-gp) activity and reduced production of intracellular reactive oxygen species (ROS).