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Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer.

ABSTRACT: Chimeric inhibitors, which merge two drug pharmacophores in a single molecule have become a prominent approach for the design of novel anticancer compounds. Here, we examined animacroxam, which combines histone deacetylase (HDAC) inhibitory and cytoskeleton-interfering pharmacophores, in testicular germ cell tumors (TGCT). The effectiveness of animacroxam was compared to that of the commonly applied chemotherapeutic cisplatin as well as the clinically approved HDAC inhibitor vorinostat. The antineoplastic and antiangiogenic effects of animacroxam on TGCT in vivo were assessed through exploratory animal studies and a modified chorioallantoic membrane assay, revealing that animacroxam has significant antitumor activity in TGCT. A novel positron emission tomography/MR-imaging approach was applied to determine tumor volume and glucose [2-fluoro-2-deoxy-d-glucose (18F-FDG)] uptake in TGCT tumors, revealing reduced glucose uptake in animacroxam-treated TGCTs and showing a dose-dependent suppression of glycolytic enzymes, which led to a breakdown in glycolytic energy production. Furthermore, the observed antiangiogenic effects of animacroxam were related to its ability to inhibit endothelial cell-cell communication, as the expression of gap junction-forming connexin 43 was strongly suppressed, and gap-junctional intercellular mass transport was reduced. Our data suggest that the chimeric HDAC inhibitor animacroxam may become a promising candidate for the treatment of solid cancers and may serve as an interesting alternative to platinum-based therapies.

SUBMITTER: Steinemann G

PROVIDER: S-EPMC6887589 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer.

Steinemann Gustav G Dittmer Alexandra A Schmidt Jacob J Josuttis David D Fähling Michael M Biersack Bernhard B Beindorff Nicola N Jolante Koziolek Eva E Schobert Rainer R Brenner Winfried W Müller Thomas T Nitzsche Bianca B Höpfner Michael M

Molecular oncology 20191022 12

Chimeric inhibitors, which merge two drug pharmacophores in a single molecule have become a prominent approach for the design of novel anticancer compounds. Here, we examined animacroxam, which combines histone deacetylase (HDAC) inhibitory and cytoskeleton-interfering pharmacophores, in testicular germ cell tumors (TGCT). The effectiveness of animacroxam was compared to that of the commonly applied chemotherapeutic cisplatin as well as the clinically approved HDAC inhibitor vorinostat. The anti ...[more]

PMID: 31583820

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Project description:BackgroundResistance to cisplatin-based chemotherapy is associated with poor prognosis in testicular germ cell cancer, emphasising the need for new therapeutic approaches. In this respect, the therapeutic concept of anti-angiogenesis is of particular interest. In a previous study, we presented two novel anti-angiogenic compounds, HP-2 and HP-14, blocking the tyrosine kinase activity of angiogenic growth factor receptors, such as vascular endothelial growth factor receptor-2 (VEGFR-2), and related signalling pathways in testicular cancer. In this study, we investigated the efficacy of these new compounds in platinum-resistant testicular germ cell tumours (TGCTs), in vitro and in vivo.Methods and resultsDrug-induced changes in cell proliferation of the cisplatin-sensitive TGCT cell line 2102EP and its cisplatin-resistant counterpart 2102EP-R, both expressing the VEGFR-2, were evaluated by crystal violet staining. Both compounds inhibited the growth of cisplatin-resistant TGCT cells in a dose-dependent manner. In combination experiments with cisplatin, HP-14 revealed additive growth-inhibitory effects in TGCT cells, irrespective of the level of cisplatin resistance. Anti-angiogenic effects of HP compounds were confirmed by tube formation assays with freshly isolated human umbilical vein endothelial cells. Using TGCT cells inoculated onto the chorioallantoic membrane of fertilised chicken eggs (chicken chorioallantoic membrane assay), the anti-angiogenic and anti-proliferative potency of the novel compounds was also demonstrated in vivo. Gene expression profiling revealed changes in the expression pattern of genes related to DNA damage detection and repair, as well as in chaperone function after treatment with both cisplatin and HP-14, alone or in combination. This suggests that HP-14 can revert the lost effectiveness of cisplatin in the resistant cells by altering the expression of critical genes.ConclusionThe novel compound HP-14 effectively inhibits the growth of cisplatin-resistant TGCT cells and suppresses tumour angiogenesis. Thus, HP-14 may be an interesting new agent that should be further explored for TGCT treatment, especially in TGCTs that are resistant to cisplatin.

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Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer.

Publications

Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer.

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