Deubzer Hedwig E, Ehemann Volker, Westermann Frank, Heinrich Ralf, Mechtersheimer Gunhild, Kulozik Andreas E, Schwab Manfred, Witt Olaf
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Int J Cancer. 2008 Apr 15;122(8):1891-900. doi: 10.1002/ijc.23295.
The survival rate of children with advanced neuroblastoma (NB) is dismal despite intensive multimodal therapy. The limited efficacy and the frequent and serious side effects of currently used therapeutic regimens necessitate the development of new, less toxic treatment strategies. This study shows that the histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of both established NB cell lines and primary NB cells with and without amplified MYCN at dosages lower than 20 nM. HC-toxin induces cell cycle arrest and apoptosis as well as neuronal differentiation and diminishes both colony formation and invasive growth. These cellular changes are accompanied by the transcriptional repression of cell cycle regulators of the retinoblastoma (RB) tumor suppressor network found at high levels in NBs with poor prognosis, like E2F-1 and its targets Skp2, N-myc, Mad2 and survivin. The levels of the hypophosphorylated active form of RB, and of cyclin-dependent kinase inhibitors including p15(INK4b), p16(INK4a), p21(cip1/waf-1) and p27(kip1) are increased. In conclusion, nanomolar doses of the HDACI HC-toxin cause a shift to a differentiated and benign phenotype of NB cells that is associated with an activation of the RB tumor suppressor network.
尽管采用了强化多模式疗法，晚期神经母细胞瘤（NB）患儿的生存率依然很低。目前使用的治疗方案疗效有限且频繁出现严重副作用，因此有必要开发毒性更低的新治疗策略。本研究表明，组蛋白脱乙酰酶抑制剂炭疽长蠕孢（HC）毒素在剂量低于20 nM时，可抑制已建立的NB细胞系以及有无MYCN扩增的原代NB细胞的恶性表型。HC毒素诱导细胞周期停滞和凋亡以及神经元分化，并减少集落形成和侵袭性生长。这些细胞变化伴随着视网膜母细胞瘤（RB）肿瘤抑制网络的细胞周期调节因子的转录抑制，这些调节因子在预后不良的NB中高水平存在，如E2F-1及其靶标Skp2、N-myc、Mad2和存活素。RB的低磷酸化活性形式以及包括p15（INK4b）、p16（INK4a）、p21（cip1/waf-1）和p27（kip1）在内的细胞周期蛋白依赖性激酶抑制剂的水平升高。总之，纳摩尔剂量的HDACI HC毒素会使NB细胞转变为分化型和良性表型，这与RB肿瘤抑制网络的激活有关。
