The interaction of platinum-based drugs with native biologically relevant proteins
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ORIGINAL PAPER
The interaction of platinum-based drugs with native biologically relevant proteins Christine Brauckmann & Christoph A. Wehe & Michael Kieshauer & Claudia Lanvers-Kaminsky & Michael Sperling & Uwe Karst
Received: 19 July 2012 / Revised: 30 August 2012 / Accepted: 4 September 2012 / Published online: 30 September 2012 # Springer-Verlag 2012
Abstract This study focuses on the identification of the products that are formed upon binding of therapeutically relevant platinum complexes to proteins like β-lactoglobulin A (LGA), human serum albumin (HSA), or human hemoglobin (HB). The respective proteins were incubated with the platinumbased anticancer drugs cisplatin, carboplatin, and oxaliplatin. LGA was selected as the model protein in addition to the two most abundant blood proteins HSA and HB. In case of the model protein, the effect of free thiol groups on the affinity of cisplatin, carboplatin, and oxaliplatin was investigated by means of liquid chromatography electrospray ionization timeof-flight mass spectrometry (LC/ESI-ToF-MS). The reduced form of LGA, which contains four free thiol groups more than the native LGA, shows a much higher affinity to the platinumbased drugs. By means of liquid chromatography coupled to inductively coupled plasma mass spectrometry, the reaction behavior of the platinum-based drugs towards HSA and HB was investigated under different conditions considering the
Published in the topical collection Metallomics with guest editors Uwe Karst and Michael Sperling C. Brauckmann : C. A. Wehe : M. Kieshauer : M. Sperling : U. Karst (*) Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstr. 28/30, 48149 Münster, Germany e-mail: [email protected] C. Lanvers-Kaminsky Department of Paediatric Haematology and Oncology, University Children’s Hospital, Albert-Schweitzer Campus 1 A1, 48149 Münster, Germany M. Sperling European Virtual Institute for Speciation Analysis (EVISA), Mendelstr.11, 48149 Münster, Germany
chloride concentration (4 or 100 mM) and the incubation time (24 and 48 h). In case of carboplatin, less than 6 % proteinbound platinum was detected. However, both cisplatin and oxaliplatin display a high affinity to the proteins investigated. Further information was obtained by means of LC/ESI-ToFMS. In case of oxaliplatin, the complex [Pt(DACH)]2+ (DACH0C6N2H14) was identified interacting with HSA and HB. For cisplatin, different results were observed for the two proteins. The complex [Pt(NH3)2Cl]+ interacted predominantly with HSA and [Pt(NH3)2]2+ with HB. Keywords Cisplatin . Carboplatin . Oxaliplatin . Human albumin . Human hemoglobin . ESI-MS
Introduction Cisplatin, carboplatin, and oxaliplatin are the most commonly used platinum-based anticancer drugs worldwide. Each of these drugs has different dose-limiting side effects. In the case of cisplatin, nephrotoxicity and ototoxicity may be observed while oxaliplatin predominantly leads to neurotoxicity and carboplatin causes myelosuppression [1, 2]. All drugs are administered intravenously, but
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