Synergistic interaction between cisplatin and gemcitabine in neuroblastoma cell lines and multicellular tumor spheroids

• Published in: Cancer letters 2012-06, Vol.319 (1), p.23-30
• Main Authors: Besançon, Odette G, Tytgat, Godelieve A.M, Meinsma, Rutger, Leen, René, Hoebink, Jerry, Kalayda, Ganna V, Jaehde, Ulrich, Caron, Huib N, van Kuilenburg, André B.P
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Cancer; Cancer therapies; Cell Line, Tumor; Cisplatin; Cisplatin - pharmacology; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxyribonucleic acid; DNA; DNA repair; Drug interactions; Drug Screening Assays, Antitumor; Drug Synergism; Gemcitabine; Hematology, Oncology and Palliative Medicine; Humans; mechanism of action; Neuroblastoma; Neuroblastoma - drug therapy; platinum; proteins; Ribonucleotide reductase; Spheroids; Spheroids, Cellular - drug effects; synergism; Tumor Cells, Cultured; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2011.12.016

The efficacy and mechanism of action of cisplatin and gemcitabine were investigated in a panel of neuroblastoma cell lines and multicellular tumor spheroids. In neuroblastoma spheroids, the combination of cisplatin and gemcitabine induced a complete cytostasis at clinical relevant concentrations. A synergistic effect was observed when cells were coincubated with both drugs or preincubated with gemcitabine first. These administration sequences resulted in NASS cells in decreased ERCC1 and XPA expression, two key proteins of the NER DNA repair system, and increased platinum adduct formation in DNA. Most of these phenomena were not observed in SJNB8 cells which might explain the lack of synergy between cisplatin and gemcitabine in SJNB8 cells. Our results showed favorable interactions between cisplatin and gemcitabine in 4 out of 5 cell lines. Therefore, we feel that inclusion of gemcitabine into cisplatin-containing regiments might be a promising new strategy for the treatment of neuroblastoma.