Abstract
The platinum drugs cisplatin, carboplatin, and oxaliplatin are highly utilized in the clinic and as a consequence have been extensively studied in the laboratory setting, sometimes by generating fluorophore-tagged analogs. Here, we synthesized two Pt(II) complexes containing ethane-1,2-diamine ligands linked to a BODIPY fluorophore, and compared their biological activity with previously reported Pt(II) complexes conjugated to carboxyfluorescein and carboxyfluorescein diacetate. The cytotoxicity and DNA damage capacity of Pt–fluorophore complexes was compared to cisplatin, and the Pt–BODIPY complexes were found to be more cytotoxic with reduced cytotoxicity in cisplatin-resistant cells. Microscopy revealed a predominately cytosolic localization, with nuclear distribution at higher concentrations. Spheroids grown from parent and resistant cells revealed penetration of Pt–BODIPY into spheroids, and retention of the cisplatin-resistant spheroid phenotype. While most activity profiles were retained for the Pt–BODIPY complexes, accumulation in resistant cells was only slightly affected, suggesting that some aspects of Pt–fluorophore cellular pharmacology deviate from cisplatin.
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Acknowledgments
This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. We thank George Leiman for editorial assistance, and Robert O’Connor (NIDDK) for assistance with NMR acquisition.
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J. C. Jagodinsky and A. Sulima contributed equally to this work.
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Jagodinsky, J.C., Sulima, A., Cao, Y. et al. Evaluation of fluorophore-tethered platinum complexes to monitor the fate of cisplatin analogs. J Biol Inorg Chem 20, 1081–1095 (2015). https://doi.org/10.1007/s00775-015-1290-2
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DOI: https://doi.org/10.1007/s00775-015-1290-2