Frommann Kristin, Appl Birgit, Hundsdoerfer Patrick, Reinshagen Konrad, Eschenburg Georg
Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
J Pediatr Surg. 2018 Oct;53(10):2059-2064. doi: 10.1016/j.jpedsurg.2018.01.012. Epub 2018 Jan 31.
In spite of good initial therapy response neuroblastomas often spread to distant organs or relapse after periods of remission. Dysregulation of apoptosis, a hallmark of cancer, is often effected by elevated levels of antiapoptotic signals leading to resistance against chemotherapeutic drugs. Inhibitors of apoptosis proteins (IAPs) are crucial cellular apoptosis regulators. Targeting IAPs with Smac mimetics has been demonstrated as a promising strategy for treatment of neuroblastoma and other tumors.
In paired neuroblastoma cell lines, obtained from the same patient at time of diagnosis (CHLA-15) and postchemotherapy during progressive disease (CHLA-20), expression of crucial IAPs was determined. Furthermore, effects of vincristine on viability, cytotoxicity, apoptosis induction and caspase-3/7 activation were determined.
Cellular IAP-1 (cIAP-1) and X-linked IAP (XIAP) expression was increased in cell line CHLA-20. Moreover, biological effects of vincristine were significantly lower in these cells. Treatment of cells with Smac mimetic LCL161 increased the effects of vincristine in CHLA-15 cells and more importantly was able to overcome vincristine resistance in CHLA-20 cells.
These findings demonstrate the potential of Smac mimetics for the development of novel therapeutic approaches for the treatment of relapsed/resistant neuroblastoma.
尽管初始治疗反应良好，但神经母细胞瘤常扩散至远处器官或在缓解期后复发。细胞凋亡失调是癌症的一个标志，通常由抗凋亡信号水平升高导致对化疗药物产生耐药性。凋亡抑制蛋白（IAPs）是关键的细胞凋亡调节因子。用Smac模拟物靶向IAPs已被证明是治疗神经母细胞瘤和其他肿瘤的一种有前景的策略。
在成对的神经母细胞瘤细胞系中，这些细胞系分别在诊断时（CHLA - 15）和疾病进展期化疗后（CHLA - 20）从同一患者获取，测定关键IAPs的表达。此外，还测定了长春新碱对细胞活力、细胞毒性、凋亡诱导和半胱天冬酶 - 3/7激活的影响。
细胞系CHLA - 20中细胞IAP - 1（cIAP - 1）和X连锁IAP（XIAP）的表达增加。此外，长春新碱在这些细胞中的生物学效应显著降低。用Smac模拟物LCL161处理细胞可增强长春新碱在CHLA - 15细胞中的作用，更重要的是能够克服CHLA - 20细胞对长春新碱的耐药性。
这些发现证明了Smac模拟物在开发治疗复发/耐药神经母细胞瘤新治疗方法方面的潜力。
