A major hallmark of cancer cells that confer resistance to radiation treatment is overexpression of several survival pathways, including the heat-shock-protein 90 (Hsp90) chaperone system and PI3K/mTOR pathway. Our team investigates a range of novel low-molecular weight inhibitors of Hsp90, PI3K and/or mTOR proteins as possible radiosensitizers in various cancer entities. In preclinical studies involving a broad spectrum of in vitro and in vivo assays, e.g. cell survival, morphology, protein expression, cell cycle progression, migration/invasion, DNA microarrays, mouse xenograft, etc., we explore the mechanisms of chemo- and radiation sensitivity of tumor cells. We also analyze the impact of the most frequently mutated tumor suppressors p53 and PTEN in the chemo- and radiation response of tumors. The experiments are intended to test the concept of molecular targeting of survival pathways as a strategy for improving radiotherapy outcome.
Memmel, S., Sukhorukov, V.L., Höring, M., Westerling, K., Fiedler, V., Katzer, A., Krohne, G., Flentje, M., Djuzenova, C.S. (2014) Cell surface area and membrane folding in glioblastoma cell lines differing in PTEN and p53 status. PLoS One 9:e87052.
Hartmann, S., Günther, N., Biehl, M., Katzer, A., Kuger, S., Worschech, E., Sukhorukov, V.L., Krohne, G., Zimmermann, H., Flentje M., Djuzenova C.S. (2013) Hsp90 inhibition by NVP-AUY922 and NVP-BEP800 decreases migration and invasion of irradiated normoxic and hypoxic tumor cell lines. Cancer Lett. 331:200-210.
Kuger, S., Graus, D., Brendtke, R., Günther, N., Katzer, A., Lutyj, P., Polat, B., Chatterjee, M., Sukhorukov, V.L., Flentje, M., Djuzenova, C.S. (2013) Radiosensitization of Glioblastoma Cell Lines by the Dual PI3K- and mTOR-Inhibitor NVP-BEZ235 Depends on Drug-Irradiation Schedule. Transl. Oncol. 6:169-179.
Djuzenova, C.S., Blassl, C., Roloff, K., Kuger, S., Katzer, A., Niewidok, N., Günther, N., Polat, B., Sukhorukov, V.L, Flentje, M. (2012) Hsp90 inhibitor NVP-AUY922 enhances radiation sensitivity of tumor cell lines under hypoxia. Cancer Biol. Ther. 13:425-434.
Stingl, L., Stühmer, T., Chatterjee, M., Jensen, M.R., Flentje, M., Djuzenova, C.S. (2010) Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction. Brit. J. Cancer 102:1578-1591.