Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Acta Neuropathol Commun. 2014 Mar 31;2:31. doi: 10.1186/2051-5960-2-31.
Notch and Hedgehog signaling have been implicated in the pathogenesis and stem-like characteristics of glioblastomas, and inhibitors of the pathways have been suggested as new therapies for these aggressive tumors. It has also been reported that targeting both pathways simultaneously can be advantageous in treating glioblastoma neurospheres, but this is difficult to achieve in vivo using multiple agents. Since arsenic trioxide has been shown to inhibit both Notch and Hedgehog in some solid tumors, we examined its effects on these pathways and on stem cell phenotype in glioblastoma.
We found that arsenic trioxide suppresses proliferation and promotes apoptosis in three stem-like glioblastoma neurospheres lines, while inhibiting Notch and Hedgehog target genes. Importantly, arsenic trioxide markedly reduced clonogenic capacity of the tumor neurospheres, and the stem-like CD133-positive fraction was also diminished along with expression of the stem cell markers SOX2 and CD133.
Our results suggest that arsenic trioxide may be effective in targeting stem-like glioblastoma cells in patients by inhibiting Notch and Hedgehog activity.
Notch 和 Hedgehog 信号通路与神经胶质瘤的发病机制和干细胞样特征有关，这些通路的抑制剂被认为是治疗这些侵袭性肿瘤的新方法。据报道，同时靶向两条通路在治疗神经胶质瘤球体方面可能具有优势，但使用多种药物在体内很难实现这一目标。由于三氧化二砷已被证明可抑制某些实体瘤中的 Notch 和 Hedgehog，因此我们研究了它对这些通路以及神经胶质瘤中干细胞表型的影响。
我们发现三氧化二砷可抑制三种干细胞样神经胶质瘤球体系的增殖并促进其凋亡，同时抑制 Notch 和 Hedgehog 靶基因。重要的是，三氧化二砷显著降低了肿瘤神经球体的集落形成能力，同时干细胞标记物 SOX2 和 CD133 的表达也减少了，CD133 阳性的干细胞样分数也减少了。
我们的结果表明，三氧化二砷通过抑制 Notch 和 Hedgehog 活性可能对靶向神经胶质瘤干细胞的患者有效。
