Abstract 1705: Comparison of uptake mechanisms for different anthracyclines in leukemic cells

Abstract

Abstract Aims: The mechanisms behind cellular anthracycline uptake are not completely understood. It is of great interest to gain more insight into cellular uptake mechanisms since this could possibly be used to increase the selectivity of the drugs. We therefore compared the uptake of 5 different anthracyclines, daunorubicin (DNR), doxorubicin (DOX), epirubicin (EPI), idarubicin (IDA), and pirarubicin (PIRA) by leukemic cells and also investigated the possible involvement of specific carriers. Methods: HL-60 cells were incubated with increasing concentrations of anthracyclines for 1 hour and cellular drug uptake was determined. The cells were also preincubated with various protein inhibitors or nucleosides and then with the anthracyclines after which drug uptake was determined with HPLC. Apoptosis was determined with propidium iodine staining and flow cytometry. Results: Of all anthracyclines studied DNR, IDA and PIRA had the highest cellular uptake with a sharp increase in uptake at extracellular concentrations > 1 µM. Uptake of DOX, DNR and IDA was greatly reduced at 0°C. Suramin, a purinergic-2-receptor inhibitor, strongly inhibited the uptake of all anthracyclines except PIRA and dipyridamole, a nucleoside transport inhibitor, only inhibited the uptake of DNR. The addition of nucleosides reduced the uptake of DNR, IDA and PIRA. Conclusion: Our results suggest different uptake mechanisms for various anthracyclines. We found evidence for carrier mediated uptake mechanisms, the data support the involvement of the nucleoside transporter family. Furthermore, our results also indicate an involvement of purinergic-2-receptor signalling in anthracycline uptake. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1705. doi:10.1158/1538-7445.AM2011-1705