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.
Highlights
Molecular hybridization has emerged as a smart and effective approach in the development of novel anticancer compounds
We developed an advanced chorioallantoic membrane (CAM) assay by employing state-of-the-art magnetic resonance imaging (MRI)/positron emission tomography (PET) to precisely calculate tumor volume and to perform metabolic assessments of individual tumors in a noninvasive manner (Ma et al, 2015; Warnock et al, 2013)
The antineoplastic and antiangiogenic effects of the novel chimeric histone deacetylase (HDAC) inhibitor animacroxam were investigated in xenografted models of testicular germ cell tumors (TGCTs) and the underlying modes of action were deciphered
Summary
Molecular hybridization has emerged as a smart and effective approach in the development of novel anticancer compounds. Two drug pharmacophores are merged to one single molecule, which acts on two distinct cellular targets This contrasts with combination therapies, where two or more active compounds are given sequentially or as a cocktail to achieve (over-)additive antitumoral effects. The risk of drug–drug interactions and the occurrence of adverse or unwanted side effects require a complex dose adjustment to avoid therapeutic ineffectiveness. To overcome these limitations, several research groups started to develop so-called chimeric compounds. Hybrid compounds combining HDAC-inhibiting moieties with other cancer targets have been developed to overcome drug resistance and to synergistically enhance the anticancer activity of these novel compounds (Schobert and Biersack, 2017)
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