Abstract
Contrasting agents (CAs) that are administered to patients during magnetic resonance imaging to facilitate tumor identification are generally considered harmless. However, gadolinium (Gd) based contrast agents can be retained in the body, inflicting specific cell line cytotoxicity. We investigate the effect of Gadopentatic acid (Gd-DTPA) on human breast adenocarcinoma MCF-7 cells. These cells exhibit a toggle switch response: exposure to 0.1 and 1 mM concentrations of Gd-DTPA enhances proliferation, which is hindered at a higher 10 mM concentration. Proliferation is enhanced when cells transition to 3D morphologies in post confluent conditions. The proliferation dependence on the concentration of CA is absent for Hs 578T and MDA-MB-231 triple negative cell lines. MCF-7 cells reveal a double toggle switch related to the expression of VEGF, which goes through high–low–high downregulation when cells are exposed to 0.1, 1, and 10 mM Gd-DTPA, respectively. Finally, doxorubicin drug response is assessed, which also reveals a double toggle switch behavior, where drug cytotoxicity exhibits a nonlinear dependence on the CA concentration. A toggle switch in cell characteristics that are exposed to 1 mM of Gd-DTPA amplifies the importance of this threshold, affecting several cell behaviors if surpassed. This work emphasizes the important effects that CAs can have on cells, specifically Gd-DTPA on MCF-7 cells, and the implications for cell growth and drug response during clinical and synthetic biology procedures.
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Acknowledgements
This work is supported by a Natural Sciences and Engineering Research Council of Canada (Grant RGPIN-2014-04066) Discovery Grant (NSERC-DG), Canada Foundation for Innovation John R. Evans Leaders Fund (CFI-JELF), Ontario Research Fund Research Infrastructure (ORF-RI) grants (Grant No. 33016), the Mitacs Globalink Program and the German Academic Exchange Service (DAAD). The authors thank Dr. Juliet Daniel from Department of Biology at McMaster University for donating Hs 578T and MDA-MB-231 cells.
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AA and SM contributed equally to this work. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
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Abdel Fattah, A.R., Mishriki, S., Kammann, T. et al. Gadopentatic acid affects in vitro proliferation and doxorubicin response in human breast adenocarcinoma cells. Biometals 31, 605–616 (2018). https://doi.org/10.1007/s10534-018-0109-3
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DOI: https://doi.org/10.1007/s10534-018-0109-3