Metabolism and transport of flavonoid-based compounds in human breast cancer cells: impact on therapy

Supervisor: Walter Jäger, Department of Clinical Pharmacy and Diagnostics

Student: Stefan Brenner

Breast cancer is the major cause of cancer death in women worldwide. Epidemiological data indicate that in Europe and in the USA one woman in eight will develop this disease during her lifetime. Despite advances in early detection and treatment, breast cancer mortality rates have not decreased significantly over the past few decades. For most women diagnosed with metastatic breast cancer, low median survival durations after diagnosis are common and the goals of therapy are only focused on prolonging life, providing cancer-related symptom relief, minimizing treatment-related toxicity and improving quality of life. Hartinger and coworkers (Institute of Inorganic Chemistry, University of Vienna) synthesized novel flavonoid-derived metal complexes with excellent antiproliferative activity against various cell lines including breast cancer cells. As the therapeutic potential of these compounds will strongly correlate with their intracellular drug concentrations in tumor cells, the objective of this thesis is the time- and concentration-dependent formation of metabolites in hormone-dependent and hormone-independent human breast cancer cell lines. Furthermore, the chemical structures of the isolated flavonoid metabolites will be determined by LC/MS/MS and NMR and their anticancer activity elucidated. Phase I/II enzymes and membrane transporters responsible for the metabolism and cellular uptake of flavonoids will be determined by using recombinant enzymes and transfected human breast cancer cell lines. Expression of drug metabolizing enzymes and transporters in the tumor cells will be measured by real-time RT-PCR, Western blotting, and microarrays.