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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Animacroxam，一种新型的双模式化合物，针对组蛋白脱乙酰基酶和睾丸生殖细胞癌细胞的细胞骨架完整性

迫切需要用于治疗包括睾丸生殖细胞肿瘤（TGCT）在内的晚期实体瘤的新方法。尤其是，对基于顺铂疗法的治疗无反应的TGCT患者需要替代疗法，因为对于该特定亚组尚无有效的药物治疗方法。在这里，我们研究了新型双模式复方安康定用于TGCT治疗的适用性。Animacroxam由抑制HDAC的异羟肟酸酯部分与具有固有的细胞骨架破坏潜能的4,5-二芳基咪唑偶联而成。Animacroxam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，细胞周期阻滞和诱导凋亡的作用。Animacroxam的IC50值介于0.22至0.42μmol/ L之间，与肿瘤细胞的顺铂敏感性无关。在顺铂敏感或耐药的TGCT细胞中，即使剂量高达10μmol/ L，也没有观察到苯甲酰胺的非特异性细胞毒性。此外，阿尼莫克沙姆诱导了癌细胞中肌动蛋白应激纤维的形成，从而证实了其咪唑部分的细胞骨架破坏和抗迁移特性。当与临床建立的HDAC抑制剂伏立诺他进行比较时，新型双模式化合物animacroxam在体外表现出优异的抗肿瘤功效。Animacroxam还可以降低体内TGCT肿瘤的肿瘤大小，这是通过对受精卵的绒毛膜尿囊膜进行异种移植实验（CAM分析）证明的。体内实验还表明该化合物具有很好的耐受性，因此，一般而言，阿尼莫克沙姆可能是有前景的TGCT创新疗法的候选药物，而对铂不敏感或难治性TGCT则更是如此。分子癌疗法；16（11）; 2364–74。©2017 AACR。