Körbel Christina, Linxweiler Maximilian, Bochen Florian, Wemmert Silke, Schick Bernhard, Meyer Markus, Maurer Hans, Menger Michael D, Zimmermann Richard, Greiner Markus
Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, saabrucken, Germany.
Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Hospital, Homburg/Saar, saabrucken, Germany.
Biomol Concepts. 2018 May 19;9(1):53-63. doi: 10.1515/bmc-2018-0006.
Treatment with analogues of the SERCA-inhibitor Thapsigargin is a promising new approach for a wide variety of cancer entities. However, our previous studies on various tumor cells suggested resistance of SEC62 over-expressing tumors to this treatment. Therefore, we proposed the novel concept that e.g. lung-, prostate-, and thyroid-cancer patients should be tested for SEC62 over-expression, and developed a novel therapeutic strategy for a combinatorial treatment of SEC62 over-expressing tumors. The latter was based on the observations that treatment of SEC62 over-expressing tumor cells with SEC62-targeting siRNAs showed less resistance to Thapsigargin as well as a reduction in migratory potential and that the siRNA effects can be mimicked by the Calmodulin antagonist Trifluoperazine. Therefore, the combinatorial treatment of SEC62 over-expressing tumors was proposed to involve Thapsigargin and Trifluoperazine. Here, we addressed the impact of Thapsigargin and Trifluoperazine in separate and combined treatments of heterotopic tumors, induced by inoculation of human hypopharyngeal squamous cell carcinoma (FaDu)-cells into the mouse flank. Seeding of the tumor cells and/or their growth rate were significantly reduced by all three treatments, suggesting Trifluoperazine is a small molecule to be considered for future therapeutic strategies for patients, suffering from Sec62-overproducing tumors.
使用SERCA抑制剂毒胡萝卜素类似物进行治疗是针对多种癌症实体的一种有前景的新方法。然而，我们之前对各种肿瘤细胞的研究表明，过表达SEC62的肿瘤对这种治疗具有抗性。因此，我们提出了一个新的概念，即例如肺癌、前列腺癌和甲状腺癌患者应检测SEC62的过表达情况，并开发了一种针对过表达SEC62肿瘤的联合治疗新策略。后者基于以下观察结果：用靶向SEC62的小干扰RNA（siRNA）处理过表达SEC62的肿瘤细胞，对毒胡萝卜素的抗性降低，迁移潜能也降低，并且钙调蛋白拮抗剂三氟拉嗪可以模拟siRNA的作用。因此，有人提出过表达SEC62肿瘤的联合治疗应包括毒胡萝卜素和三氟拉嗪。在此，我们探讨了毒胡萝卜素和三氟拉嗪在单独及联合治疗将人下咽鳞状细胞癌（FaDu）细胞接种到小鼠侧腹诱导的异位肿瘤中的作用。所有三种治疗方法均显著降低了肿瘤细胞的接种和/或其生长速率，这表明三氟拉嗪是一种小分子，应考虑用于未来对患有Sec62过表达肿瘤患者的治疗策略。
