Lovat Penny E, Oliverio Serafina, Corazzari Marco, Ranalli Marco, Pearson Andy D J, Melino Gerry, Piacentini Mauro, Redfern Christopher P F
Northern Institute for Cancer Research, University of Newcastle Upon Tyne, Newcastle Upon Tyne NE2 4HH, UK.
Cancer Lett. 2003 Jul 18;197(1-2):157-63. doi: 10.1016/s0304-3835(03)00098-3.
Unlike 13-cis retinoic acid, the synthetic retinoid fenretinide induces apoptosis of neuroblastoma cells and in vitro acts synergistically with the chemotherapeutic drugs, cisplatin, etoposide and carboplatin. The stress-induced transcription factor GADD153 and the Bcl2-related protein Bak are upregulated in response to fenretinide. Although fenretinide is a partial retinoic acid receptor (RAR)-beta/gamma agonist, RARbeta/gamma antagonists do not block the induction of GADD153 or Bak by fenretinide. Conversely, the induction of GADD153 and Bak is blocked by antioxidants. Neither GADD153 or Bak were induced by chemotherapeutic agents but over expression of GADD153 results in increased sensitivity to fenretinide-induced apoptosis. Therefore, fenretinide induces apoptosis via RAR-dependent and -independent pathways in which the RAR-independent pathway is characterised by the reactive oxygen species-dependent induction of GADD153 and Bak. The targeting of GADD153 and Bak in neuroblastoma cells may be novel pathways for the development of drugs inducing apoptosis of neuroblastoma with improved tumour specificity.
与13 - 顺式维甲酸不同，合成类视黄醇芬维A胺可诱导神经母细胞瘤细胞凋亡，并且在体外与化疗药物顺铂、依托泊苷和卡铂协同作用。应激诱导转录因子GADD153和Bcl2相关蛋白Bak在芬维A胺作用下上调。尽管芬维A胺是一种部分视黄酸受体（RAR）-β/γ激动剂，但RARβ/γ拮抗剂并不能阻断芬维A胺对GADD153或Bak的诱导作用。相反，抗氧化剂可阻断GADD153和Bak的诱导。化疗药物不会诱导GADD153或Bak，但GADD153的过表达会导致对芬维A胺诱导的凋亡敏感性增加。因此，芬维A胺通过RAR依赖性和非依赖性途径诱导凋亡，其中RAR非依赖性途径的特征是活性氧依赖性诱导GADD153和Bak。在神经母细胞瘤细胞中靶向GADD153和Bak可能是开发具有更高肿瘤特异性的诱导神经母细胞瘤凋亡药物的新途径。
