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Characterization of chemosensitivity and resistance of human cancer cell lines to platinum(II) versus platinum(IV) anticancer agents

Hamberger, Janinaa; Liebeke, Manuela; Kaiser, Mariaa; Bracht, Karina; Olszewski, Ulrikeb; Zeillinger, Robertb; Hamilton, Gerhardb; Braun, Dagmarc; Bednarski, Patrick J.a

doi: 10.1097/CAD.0b013e32832d513b
Preclinical Reports

Platinum (Pt)(IV) complexes are thought to function as prodrugs for anticancer Pt(II) drugs. We studied two pairs of Pt(II)/Pt(IV) complexes to explore whether there were differences in their cytotoxic activities, their abilities to cause acquired resistance and their gene expression profiles in the resistant lines. Microtiter methods were used to evaluate the antiproliferative activity of cisplatin, oxoplatin, [trans-d,l-(1,2-diaminocyclo-hexane)]dichloroplatinum(II) [DACH-Pt(II)] and cis,trans-[trans-d,l-(1,2-diaminocyclo-hexane)]-dichlorodihydroxoplatinum(IV) [DACH-Pt(IV)] in a panel of 14 human cancer cell lines. Cisplatin and oxoplatin showed significant similar spectra of cytotoxicity, whereas DACH-Pt(II) and DACH-Pt(IV) did not. DACH-Pt(IV) required more than 24 h to reach full potency, whereas the other three Pt complexes achieved maximal activity in less than 24 h. The SISO cervical cell line was made four- to six-fold resistant to the four Pt complexes by weekly exposure to the respective agent. Glutathione (GSH) levels increased in all resistant lines except for the DACH-Pt(IV) resistant line. The catalytic concentrations of various redox enzymes (GSH transferase, GSH peroxidase, GSH reductase, catalase) were all unchanged in the resistant lines relative to the native line. Multidrug resistance protein 2 expression was detected in the cisplatin-resistant and oxoplatin-resistant cell lines but not in the native line. The transcription of 29 000 genes in the SISO lines resistant to either cisplatin or oxoplatin was studied by DNA-microarray methods and compared with the native line. Overall changes in gene transcription were very different between the cisplatin-resistant and oxoplatin-resistant cell lines. Thus, Pt(IV) complexes seem to have biological actions that distinguish them from their Pt(II) counterparts, even when they show cross-resistance.

aDepartment of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald

bLudwig-Boltzmann-Cluster Translational Oncology, Vienna, Austria

cRiemser Arzneimittel AG, Greifswald – Insel Riems, German

Correspondence to Dr Patrick Bednarski, PhD, Institute of Pharmacy, F.-L.-Jahn-Strasse 17, Greifswald, Germany

Tel: +49 3834 86 48 83; e-mail:

Received 31 March 2009 Revised form accepted 24 April 2009

© 2009 Lippincott Williams & Wilkins, Inc.