Animacroxam, a novel dual-mode compound targeting histone deacetylases and cytoskeletal integrity of testicular germ cell cancer cells

Novel approaches for the medical treatment of advanced solid tumors including testicular germ cell tumors (TGCT) are desperately needed. Especially, TGCT patients not responding to cisplatin-based therapy need therapeutic alternatives, as there is no effective medical treatment available for this particular subgroup. Here, we studied the suitability of the novel dual mode compound animacroxam for TGCT treatment. Animacroxam consists of a HDAC-inhibitory hydroxamate moiety coupled to a 4,5-diarylimidazole with inherent cytoskeleton disrupting potency. Animacroxam revealed pronounced antiproliferative, cell cycle arresting, and apoptosis inducing effects in TGCT cell lines with different cisplatin sensitivities. The IC50 values of animacroxam ranged from 0.22 to 0.42 µM and were not correlated to the cisplatin sensitivity of the tumor cells. No unspecific cytotoxicity of animacroxam was observed in either cisplatin sensitive or resistant TGCT cells - even at doses as high as 10 µM. Furthermore, animacroxam induced the formation of actin stress fibers in cancer cells thereby confirming the cytoskeleton disrupting and antimigratory properties of its imidazole moiety. When compared with the clinically established HDAC-inhibitor vorinostat, the novel dual mode compound animacroxam exhibited superior antitumoral efficacy in vitro. Animacroxam also reduced the tumor size of TGCT tumors in vivo, as evidenced by performing xenograft experiments on tumor bearing chorio-allantoic membranes of fertilizes chicken eggs (CAM assay). The in vivo experiments also revealed a very good tolerability of the compound and hence, aniamcroxam may be a promising candidate for innovative treatment of TGCT in general and the more so for platinum-insensitive or -refractory TGCT.

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