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.

The component of the m6A writer complex VIRMA is implicated in aggressive tumor phenotype, DNA damage response and cisplatin resistance in germ cell tumors

“…Additionally, this was further demonstrated in vivo, with reduced tumor size and angiogenesis, evaluated both macroscopically and histologically. We again highlight the versatility of the CAM assay for assessing tumor properties and response to drugs in vivo [61], also recently demonstrated for GCTs as well [62,63]. Interestingly, VIRMA knockdown resulted in significant protein expression decrease of all members of the methyltransferase complex (METTL3, the only component with catalytic activity; METTL14, which is relevant for substrate recognition, specificity and activity; and WTAP, which stabilizes the complex).…”

Comparison of Quantification of Target-Specific Accumulation of [18F]F-siPSMA-14 in the HET-CAM Model and in Mice Using PET/MRI

“…Although tumors have been already successfully established on the CAM [4,[20][21][22][23][24][25][26][27][28][29], and PET-imaging studies are available [10,24,25,[30][31][32][33][34][35], systematic analyses of their use to evaluate the biodistribution of radiopharmaceuticals and direct comparisons with the in vivo gold standard are still rare [10].…”

Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors

“…Compared with combination therapies, where different active compounds are given simultaneously or sequentially to address distinct cellular targets, the use of chimeric compounds offers several advantages and circumvents problems typical of combination therapies, such as different drug solubilities or physical incompatibilities which may lead to precipitation or drug inactivation. In addition, the risk of drug-drug interactions or the occurrence of concomitant adverse or unwanted side effects, which often require a complex dose adjustment, can be avoided when using chimeric inhibitors instead [1][2][3].…”