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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.

journal_name

Mol Oncol

journal_title

Molecular oncology

authors

Steinemann G,Dittmer A,Schmidt J,Josuttis D,Fähling M,Biersack B,Beindorff N,Jolante Koziolek E,Schobert R,Brenner W,Müller T,Nitzsche B,Höpfner M

doi

10.1002/1878-0261.12582

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

2679-2696

issue

12

eissn

1574-7891

issn

1878-0261

journal_volume

13

pub_type

杂志文章

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