Fluorescence image guided surgical resection (FIGR) of high grade gliomas (HGGs) takes advantage of the accumulation of the tracer protoporphyrin IX (PpIX) in glioma cells following administration of 5-aminolevulinic acid (5-ALA). Occasionally, PpIX fluorescence intensity may be insufficient, thus compromising the efficacy and precision of the surgical intervention. The cause for the signal variation is unclear and strategies to improve the intensity of PpIX fluorescence are considered necessary. We have previously shown that differential expression of the epidermal growth factor receptor in glioblastoma cells affects PpIX fluorescence. Herein, we investigated other factors impairing PpIX accumulation and pharmacological treatments able to enhance PpIX fluorescence in glioblastoma cells displaying lower signal. In the present study we demonstrate that presence of serum in cell culture medium and differences in cellular confluence can negatively influence PpIX accumulation in U87 cell lines. We hypothesized that PpIX fluorescence intensity results from the interplay between the metabolic clearance of PpIX mediated by ferrochelatase (FECH) and heme oxygenase-1 (HO-1) and the cellular efflux of PpIX through the ATP-binding cassette subfamily G member 2 (ABCG2). Based on the availability of compounds targeting these proteins and inhibiting them, in this study we used modulators such as genistein, an isoflavone able to inhibit ABCG2; deferoxamine, which chelate iron ions impairing FECH activity and tin protoporphyrin IX (SnPP), the specific HO-1 inhibitor. Finally, we showed the efficacy of a precisely tuned pharmacological treatment in increasing PpIX accumulation and consequently fluorescence in glioblastoma cells. This strategy may translate in more sensitive tracing of tumor cells in-vivo and improved FIGR of HGGs and possibly low grade gliomas (LGGs).

中文翻译：

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有关“原卟啉IX示踪剂荧光调制以改善脑肿瘤细胞系可视化”的勘误。

施用5-氨基乙酰丙酸（5-ALA）后，高级别神经胶质瘤（HGG）的荧光图像引导手术切除（FIGR）利用了示踪原卟啉IX（PpIX）在神经胶质瘤细胞中的积累。有时，PpIX荧光强度可能不足，从而损害了手术干预的有效性和准确性。信号变化的原因尚不清楚，因此认为必须采取提高PpIX荧光强度的策略。先前我们已经表明，胶质母细胞瘤细胞中表皮生长因子受体的差异表达会影响PpIX荧光。在本文中，我们研究了其他损害PpIX积累的因素以及能够增强显示较低信号的胶质母细胞瘤细胞中PpIX荧光的药物治疗。在本研究中，我们证明细胞培养基中血清的存在和细胞汇合的差异会对U87细胞系中的PpIX积累产生负面影响。我们假设PpIX荧光强度是由铁螯合酶（FECH）和血红素加氧酶-1（HO-1）介导的PpIX的代谢清除与通过ATP结合盒亚家族G成员2（ABCG2）的细胞外排之间的相互作用造成的）。根据靶向这些蛋白并抑制它们的化合物的可用性，在本研究中，我们使用了诸如染料木黄酮（一种能够抑制ABCG2的异黄酮）等调节剂。去铁胺，螯合铁离子会削弱FECH活性，锡原卟啉IX（SnPP）是一种特殊的HO-1抑制剂。最后，我们显示了精确调整的药理学疗法在增加胶质母细胞瘤细胞中PpIX积累并因此增加荧光方面的功效。该策略可以转化为体内更​​敏感的肿瘤细胞示踪，并改善了HGG和可能的低度神经胶质瘤（LGG）的FIGR。