Department of Internal Medicine, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
J Neurooncol. 2010 Apr;97(2):171-85. doi: 10.1007/s11060-009-0010-6. Epub 2009 Sep 20.
TNF-related apoptosis-inducing ligand (TRAIL), a promising novel anti-cancer cytokine of the TNF superfamily, and Bortezomib, the first-in-class clinically used proteasome inhibitor, alone or in combination have been shown to efficiently kill numerous tumor cell lines. However, data concerning primary human tumor cells are very rare. Using primary esthesioneuroblastoma cells we analyzed the anti-tumor potential and the mechanism employed by Bortezomib in combination with TRAIL for the treatment of this rare but aggressive tumor. Expression of components of the TRAIL pathway was analyzed in tumor specimens and isolated primary tumor cells at the protein level. Cells were treated with TRAIL, Bortezomib, and a combination thereof, and apoptosis induction was quantified. Clonogenicity assays were performed to elucidate the long-term effect of this treatment. Despite expressing all components of the TRAIL pathway, freshly isolated primary esthesioneuroblastoma cells were completely resistant to TRAIL-induced apoptosis. They could, however, be very efficiently sensitized by subtoxic doses of Bortezomib. The influence of Bortezomib on the TRAIL pathway was analyzed and showed upregulation of TRAIL death receptor expression, enhancement of the TRAIL death-inducing signaling complex (DISC), and downregulation of anti-apoptotic proteins of the TRAIL pathway. Of clinical relevance, TRAIL-resistant primary tumor cells could be repeatedly sensitized by Bortezomib, providing the basis for repeated clinical application schedules. This is the first report on the highly synergistic induction of apoptosis in primary esthesioneuroblastoma cells by Bortezomib and TRAIL. This combination, therefore, represents a promising novel therapeutic option for esthesioneuroblastoma.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是 TNF 超家族中一种有前途的新型抗癌细胞因子，硼替佐米是首个临床应用的蛋白酶体抑制剂，单独或联合使用已被证明能有效地杀死许多肿瘤细胞系。然而，关于原代人肿瘤细胞的数据非常罕见。我们使用原代嗅神经母细胞瘤细胞分析了硼替佐米联合 TRAIL 治疗这种罕见但侵袭性肿瘤的抗肿瘤潜力和作用机制。在蛋白水平上分析了肿瘤标本和分离的原代肿瘤细胞中 TRAIL 途径的组成部分的表达。用 TRAIL、硼替佐米和它们的组合处理细胞，并定量诱导细胞凋亡。进行集落形成实验以阐明这种治疗的长期效果。尽管表达了 TRAIL 途径的所有组成部分，新鲜分离的原代嗅神经母细胞瘤细胞对 TRAIL 诱导的凋亡完全耐药。然而，亚毒性剂量的硼替佐米可以非常有效地使它们敏感化。分析了硼替佐米对 TRAIL 途径的影响，结果显示 TRAIL 死亡受体表达上调，增强了 TRAIL 死亡诱导信号复合物（DISC），并下调了 TRAIL 途径的抗凋亡蛋白。具有临床意义的是，硼替佐米可使 TRAIL 耐药的原代肿瘤细胞反复敏感化，为反复临床应用方案提供了基础。这是首次报道硼替佐米和 TRAIL 可高度协同诱导原代嗅神经母细胞瘤细胞凋亡。因此，这种联合治疗代表了嗅神经母细胞瘤的一种很有前途的新治疗选择。
