Renna Cristiano, Salaroli Roberta, Cocchi Claudia, Cenacchi Giovanna
Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.
PLoS One. 2015 Apr 2;10(4):e0124149. doi: 10.1371/journal.pone.0124149. eCollection 2015.
Diphtheria toxin-like ADP-ribosyltransferases 1 and 5 (ARTD-1, ARTD-5) are poly ADP-ribose enzymes (PARP) involved in non-homologous end-joining (NHEJ), which is the major pathway of double-strand break (DSB) repair. In addition, ARTD-5, or Tankyrase (TNKS), is a positive regulator of the WNT signaling implicated in the development and biological behavior of many neoplasms, such as Medulloblastoma (MB), in which radiotherapy is an essential part of the treatment. The use of radiosensitizing agents may improve the therapeutic index in MB patients by increasing the efficacy of radiotherapy, while reducing toxicity to the neuroaxis. ARTD-5 seems to be a good molecular target for improving the current treatment of MB. In this study, we used the small molecule XAV939, a potent ARTD-5 inhibitor with a slight affinity for ARTD-1, in different human MB cell lines. XAV939 inhibited the WNT pathway and DNA-PKcs in our MB cells, with many biological consequences. The co-administration of XAV939 and ionizing radiations (IR) inhibited MB cells proliferation and clonogenic capacity, decreased their efficacy in repairing DNA damage, and increased IR-induced cell mortality. In conclusion, our in vitro data show that XAV939 could be a very promising small molecule in MB treatment, and these results lay the basis for further in vivo studies with the aim of improving the current therapy available for MB patients.
白喉毒素样ADP核糖基转移酶1和5（ARTD - 1、ARTD - 5）是参与非同源末端连接（NHEJ）的多聚ADP核糖酶（PARP），NHEJ是双链断裂（DSB）修复的主要途径。此外，ARTD - 5，即端锚聚合酶（TNKS），是WNT信号通路的正向调节因子，与许多肿瘤（如髓母细胞瘤（MB））的发生发展及生物学行为有关，放疗是MB治疗的重要组成部分。使用放射增敏剂可能通过提高放疗疗效、降低对神经轴的毒性来改善MB患者的治疗指数。ARTD - 5似乎是改善当前MB治疗的一个良好分子靶点。在本研究中，我们在不同的人MB细胞系中使用了小分子XAV939，它是一种对ARTD - 1亲和力较弱的强效ARTD - 5抑制剂。XAV939在我们的MB细胞中抑制了WNT通路和DNA - PKcs，并产生了许多生物学效应。XAV939与电离辐射（IR）联合使用可抑制MB细胞增殖和克隆形成能力，降低其修复DNA损伤的能力，并增加IR诱导的细胞死亡率。总之，我们的体外数据表明XAV939在MB治疗中可能是一种非常有前景的小分子，这些结果为进一步开展旨在改善MB患者现有治疗的体内研究奠定了基础。
