Abstract 4652: Proteomic profiling of platinum based anticancer drugs.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Carboplatin, cisplatin and oxaliplatin are structurally similar anticancer drugs and their mechanism of action is permanent coordination to DNA and interfering with DNA repair. However, these drugs have different anticancer activities in human tumors, adverse effects and dose limiting toxicities. Therefore, we performed complex proteomic profiling in order to characterize cellular effects of all three platinum based anticancer drugs. To identify the molecular basis of different pharmacological properties, expressional characteristics of cells exposed to vincristine and daunorubicin were used in parallel as prototypes of drugs with different mechanism of action. T-lymphoblastic leukemia CCRF-CEM cells were treated with 5x IC50 concentrations of individual drugs for time equivalent to half-time to induction apoptosis. Untreated (control) cells were cultured with heavy amino acid labeled media in order to enable relative quantification of peptide expression using SILAC technology, LC-MS/MS and LC-MALDI-TOF/TOF. Results were processed by Proteinscape software equipped by Mascot and Phenyx analytical algorithms. We identified 646 ± 133 proteins by ESI and 312 ± 85 proteins by MALDI in average of all fifteen replicates. Identified results were further processed by in-house written script to remove outlier peptides and to normalize individual runs. All replicates were summed, and statistic analysis was done. To see up- and down- regulated proteins, the hierarchical clustering and PCA analysis was performed. Hierarchical clustering revealed that cisplatin and carboplatin shares the same cluster what is conclusive with literature. Surprisingly, the cluster of daunorubicin and vincristine was close to cisplatin and carboplatin and the oxaliplatin was in the separated cluster from rest of four drugs. PCA analysis revealed 30 proteins with contribution higher than 1 %. The highest contribution (7.5 %) to drug clustering have proteins involved in DNA remodeling. These proteins could be used as specific biomarkers of therapy by platinum based compounds. Citation Format: Petr Dzubak, Tomas Ozdian, Dusan Holub, Gabriela Rylova, Jiri Rehulka, Madhusudhan kollareddy, Daniela Mlcuchova, Marian Hajduch. Proteomic profiling of platinum based anticancer drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4652. doi:10.1158/1538-7445.AM2013-4652