The role of membrane transporters in the molecular effects of azanucleosides and in the context of epigenetic cancer therapy

• Applicant: Dr. Maria Rius-Montraveta
• Subject Area: Pharmacology ; Cell Biology
• Term: from 2010 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 188789261

Chemotherapeutic agents must enter into cells and accumulate intracellularly to reach sufficient thera-peutic concentrations. Reduced uptake into cells or increased efflux from cells causes resistance to these agents, which results in failure of treatment. 5-Azacytidine and 2’-deoxy-5-azacytidine (decita-bine) are two closely related cytidine analogues that function as DNA methyltransferase inhibitors and represent the most advanced epigenetic drugs. While both drugs have found increasing clinical use for the treatment of myelodysplastic syndrome (MDS) and of acute myeloid leukemia (AML), clinical resistances are common. At the present, the transport mechanisms that control the uptake and efflux of this drug and its metabolites in cancer cells are unknown. The main goal of the present project is to identify the drug membrane transporters that can interact with 5-azacytidine in leukemia cells and in primary bone marrow blasts from AML patients. To this end, the expression and functional properties of the transporters for 5-azacytidine are going to be analyzed in these cell types. This approach should provide the basis for the identification of those transporters relevant in cancer cells as potential markers for the efficiency of treatment with DNA methyltransferase inhibitors in patient samples. At last, special attention is given to the epigenetic regulation and modulation of nucleoside transporter expression for a deeper understanding of the 5-azacytidine transport in drug resistant cells.

• DFG Programme: Research Grants