Charakterisierung der Wirkmechanismen des neuartigen, dual wirksamen HDAC-Inhibitors "Animacroxam" am Beispiel testikulärer Keimzelltumore [thesis]

Gustav Steinemann, Universitätsbibliothek Der FU Berlin
The most common malignancy in males between 20 and 45 years of age is the testicular germ cell tumor (TGCT). Using platin-based chemotherapy, up to 80 percent of the patients can be cured. However, the remaining 20 percent often develop cisplatin resistance, which reduces the five-year survival rate considerably. Therefore, this young patient group urgently needs the development of new treatment strategies. As a promising approach in tumor therapy, the development of dual-mode inhibitors has
more » ... e inhibitors has gained increased attention over the last years. In this study, the new dual-mode inhibitor animacroxam, comprising of a histonedeacetylase- (HDAC) and a cytoskeleton-inhibitory pharmacophore, is investigated for the first time to assess the effectiveness in TGCT. The effect of animacroxam is compared with the effects of the gold standard on TGCT therapy, namely cisplatin and the established HDAC-inhibitor (HDACi) vorinostat. Animacroxam shows a dose-dependent proliferation inhibition in TGCT cells up to 95 percent, irrespective of the cisplatin sensitivity of the investigated cell lines. Additionally, animacroxam does not induce unspecific cytotoxicity. Cell-cycle investigations reveal a pronounced accumulation of cells in the G0/G1-phase of the cell cycle after incubation with animacroxam in the investigated TGCT cell lines. Animacroxam is also able to induce the formation of actin-stressfibers, thereby directly targeting the cytoskeleton of the TGCT cells. Furthermore, the migration of TGCT cells is significantly inhibited after incubation with animacroxam. Investigations on the glucose metabolism of TGCT cells revealed that animacroxam causes a dose-dependent breakdown of cellular glycolysis. Animacroxam is also able to inhibit angiogenesis in vitro and cause a significant reduction of connexin 43 (cx43) and a concomitant inhibition of the gap-junctional intercellular communication in endothelial cells. The antineoplastic and antiangiogenic effects in vivo were investigated using an advanced chorioallantoic membrane (CAM) [...]
doi:10.17169/refubium-29001 fatcat:5ssjledpevcl7el5f4e2m5yra4