Department of Paediatric Haematology and Oncology, University Children's Hospital Jena, Jena, Germany.
Cancer Chemother Pharmacol. 2010 Aug;66(3):611-6. doi: 10.1007/s00280-010-1302-4. Epub 2010 Mar 10.
It has recently been recognised that anticancer chemotherapy can elicit an immunogenic form of apoptosis characterised by the exposure of calreticulin (CRT) on the surface of dying tumour cells, entailing an immune response that contributes to the therapeutic outcome. CRT exposure has been found to be induced by anthracyclins and oxaliplatin, but not by other proapoptotic antineoplastic agents including etoposide, camptothecin and cisplatin. In this study, we examined the histone deacetylase inhibitor vorinostat for its capability to stimulate CRT exposure in tumour cells.
Childhood tumour cells, i.e. the brain tumour cell lines PFSK and DAOY and the Ewing's sarcoma cell line CADO-ES-1, were treated with vorinostat, and CRT exposure was determined by flow cytometric analysis of CRT immunofluorescence. Combination effects of vorinostat/TRAIL and vorinostat/bortezomib were also assessed.
Vorinostat treatment induced CRT exposure in PFSK and DAOY cells, but not in caspase-8-deficient CADO-ES-1 cells. CRT exposure could be prevented by the pan-caspase inhibitor z-VAD-fmk and by brefeldin A, an inhibitor of Golgi-mediated transport.
Vorinostat has the capacity to elicit CRT exposure, suggesting its usefulness as immunogenic antitumour agent.
最近已经认识到，抗癌化疗可以引发一种免疫原性的细胞凋亡形式，其特征是死亡肿瘤细胞表面暴露钙网蛋白（CRT），从而引发有助于治疗效果的免疫反应。已经发现 CRT 暴露是由蒽环类药物和奥沙利铂诱导的，但不是由其他促凋亡的抗肿瘤药物诱导的，包括依托泊苷、喜树碱和顺铂。在这项研究中，我们研究了组蛋白去乙酰化酶抑制剂伏立诺他刺激肿瘤细胞 CRT 暴露的能力。
用伏立诺他处理儿童肿瘤细胞，即脑肿瘤细胞系 PFSK 和 DAOY 以及尤文肉瘤细胞系 CADO-ES-1，并通过 CRT 免疫荧光的流式细胞术分析来确定 CRT 暴露。还评估了伏立诺他/TRAIL 和伏立诺他/硼替佐米的联合作用。
伏立诺他处理诱导了 PFSK 和 DAOY 细胞中的 CRT 暴露，但 caspase-8 缺陷型 CADO-ES-1 细胞中没有。CRT 暴露可以被泛半胱天冬酶抑制剂 z-VAD-fmk 和 Golgi 介导的运输抑制剂布雷非德菌素 A 阻止。
伏立诺他具有诱导 CRT 暴露的能力，表明其作为免疫原性抗肿瘤药物的有用性。
