An induction of Retinol Binding Protein 4 by new platinum-based anticancer agent LA-12
| Autoři | |
|---|---|
| Rok publikování | 2011 |
| Druh | Konferenční abstrakty |
| Fakulta / Pracoviště MU | |
| Citace | |
| Popis | Cisplatin belongs to the most widely used platin-based agent used in cancer chemotherapy. However, its use is rather limited mainly due to its severe side effects and resistance (either congenital or acquired). Therefore there has been an effort made to develop a new generation of platin-based drugs. In our work, we studied the biological properties of a new anticancer agent (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum (IV) (LA-12). We followed the initial pharmacokinetic study by measuring proteomic profiles of rat plasma to identify new LA-12 target proteins which could potentially serve as markers of LA-12 treatment, response and therapy monitoring. Using a proteomic approach based on surface-enhanced laser desorption-ionization time-of-flight mass spectrometry we measured proteomic profiles of 72 samples of rat plasma characterized by one of four LA-12 doses and one of six time intervals (since rat dosage). Correlation of 92 peak clusters with platinum concentration was evaluated. We identified plasma retinol binding protein RBP4 as a protein correlating with LA-12 level in both rat plasma and plasma ultrafiltrate. The level of RBP4 was also determined in plasma of patients from LA-12 clinical evaluation by western blotting and the similar trend was shown. Molecular modeling of the RBP4/LA-12 complex was performed to investigate the potential functional cooperation of RBP4 in LA-12 transport. We described an induction of RBP4 by a new platinum-based anticancer drug LA-12 in both rat and human plasma. The induction is in agreement with known RBP4 regulation by amantadine and cisplatin. Since retinol metabolism is disrupted in many cancers and inversely associates with malignancy, these data identify a potential novel mechanism for the action of LA-12 and other similar anticancer drugs. Cisplatin belongs to the most widely used platin-based agent used in cancer chemotherapy. However, its use is rather limited mainly due to its severe side effects and resistance (either congenital or acquired). Therefore there has been an effort made to develop a new generation of platin-based drugs. In our work, we studied the biological properties of a new anticancer agent (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum (IV) (LA-12). We followed the initial pharmacokinetic study by measuring proteomic profiles of rat plasma to identify new LA-12 target proteins which could potentially serve as markers of LA-12 treatment, response and therapy monitoring. Using a proteomic approach based on surface-enhanced laser desorption-ionization time-of-flight mass spectrometry we measured proteomic profiles of 72 samples of rat plasma characterized by one of four LA-12 doses and one of six time intervals (since rat dosage). Correlation of 92 peak clusters with platinum concentration was evaluated. We identified plasma retinol binding protein RBP4 as a protein correlating with LA-12 level in both rat plasma and plasma ultrafiltrate. The level of RBP4 was also determined in plasma of patients from LA-12 clinical evaluation by western blotting and the similar trend was shown. Molecular modeling of the RBP4/LA-12 complex was performed to investigate the potential functional cooperation of RBP4 in LA-12 transport. We described an induction of RBP4 by a new platinum-based anticancer drug LA-12 in both rat and human plasma. The induction is in agreement with known RBP4 regulation by amantadine and cisplatin. Since retinol metabolism is disrupted in many cancers and inversely associates with malignancy, these data identify a potential novel mechanism for the action of LA-12 and other similar anticancer drugs. |
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