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 an 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 μmol/L 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 μmol/L. 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 chorioallantoic membranes of fertilizes chicken eggs (CAM assay). The in vivo experiments also revealed a very good tolerability of the compound, and hence, animacroxam may be a promising candidate for innovative treatment of TGCT in general and the more so for platinum-insensitive or refractory TGCT. Mol Cancer Ther; 16(11); 2364–74. ©2017 AACR.

中文翻译：

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阿尼克沙姆，一种新型双模式化合物，靶向组蛋白去乙酰化酶和睾丸生殖细胞癌细胞的细胞骨架完整性

迫切需要用于治疗晚期实体瘤的新方法，包括睾丸生殖细胞肿瘤 (TGCT)。特别是，对基于顺铂的治疗没有反应的 TGCT 患者需要治疗替代方案，因为没有针对该特定亚组的有效药物治疗。在这里，我们研究了新型双模式复方阿尼罗沙姆对 TGCT 治疗的适用性。阿尼克沙姆由 HDAC 抑制性异羟肟酸酯部分组成，该部分与具有固有细胞骨架破坏效力的 4,5-二芳基咪唑偶联。阿尼克沙姆在具有不同顺铂敏感性的 TGCT 细胞系中显示出明显的抗增殖、细胞周期阻滞和细胞凋亡诱导作用。阿尼克沙姆的 IC50 值范围为 0.22 至 0.42 μmol/L，并且与肿瘤细胞的顺铂敏感性无关。即使在高达 10 μmol/L 的剂量下，在顺铂敏感性或耐药性 TGCT 细胞中均未观察到阿尼克沙姆的非特异性细胞毒性。此外，阿尼克沙姆诱导癌细胞中肌动蛋白应力纤维的形成，从而证实了其咪唑部分的细胞骨架破坏和抗迁移特性。与临床建立的 HDAC 抑制剂伏立诺他相比，新型双模式化合物阿尼克沙姆在体外表现出优异的抗肿瘤功效。阿尼克沙姆还在体内减少了 TGCT 肿瘤的肿瘤大小，这可以通过对带有受精卵的绒毛膜尿囊膜的肿瘤进行异种移植实验（CAM 测定）来证明。体内实验还表明该化合物具有非常好的耐受性，因此，阿尼克沙姆可能是一般 TGCT 创新治疗的有希望的候选药物，对于铂不敏感或难治性 TGCT 更是如此。摩尔癌症治疗; 16(11); 2364-74。©2017 AACR。