ATO and Gossypol for GSC treatment

Glioblastoma is one of the deadliest malignancies worldwide and is virtually incurable due to its highly infiltrative growth and limited sensitivity to conventional treatment by radiochemotherapy. It is hypothesized that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. These cells are characterized by an enhanced DNA repair capacity and expression of stemness marker genes, and elimination of this population might delay or even stop tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade can efficiently target these cancer stem cells and sensitize them to chemotherapeutic drugs. Using tumor sphere lines and primary glioma cells we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the Hh/Notch inhibitor arsenic trioxide (ATO) are capable to synergistically decrease proliferation and induce cell death in combination with the natural cotton derived anticancer agent (-)-Gossypol (Gos). In contrast to GANT in combination with Gos, the ATO/Gos combination also strongly prevented sphere formation and recovery. These synergistic effects were associated with major proteomic changes indicating decreased cell movement, distortion of cell cycle and DNA repair, as well as markedly reduced stemness. Collectively, our data show that ATO and Gos, two drugs that are safe for use in humans, represent a promising targeted therapy approach for the synergistic and specific elimination of glioma stem-like cells.

胶质母细胞瘤（Glioblastoma）是全球致死率最高的恶性肿瘤之一，因其具备高度浸润性生长的生物学特性，且对放化疗等常规治疗手段敏感性极差，几乎无法治愈。研究推测，少量具有干细胞表型的细胞是肿瘤复发的主要元凶。这类细胞的特征为DNA修复能力增强，且干细胞标志物基因表达上调；清除该细胞群或可延缓甚至阻断放化疗后的肿瘤复发。本研究旨在探究：抑制刺猬信号通路（Hedgehog signaling, Hh），或联合阻断Hh/Notch通路，能否有效靶向这类癌症干细胞，并使其对化疗药物增敏。本研究通过肿瘤球系与原代胶质瘤细胞实验证实，Hh通路抑制剂GANT61（GANT）与Hh/Notch通路抑制剂三氧化二砷（ATO），与天然棉源抗癌成分(-)-棉酚（Gos）联合使用时，可协同抑制细胞增殖并诱导细胞死亡。与GANT联合Gos的方案不同，ATO联合Gos还可显著抑制肿瘤球的形成与复苏。这类协同效应与显著的蛋白质组学变化相关，具体表现为细胞运动能力减弱、细胞周期与DNA修复过程紊乱，以及干细胞性显著降低。综上，本研究数据表明，ATO与Gos这两种已被证实对人体安全的药物，可作为一种极具前景的靶向治疗策略，实现对胶质瘤干细胞样细胞的协同且特异性清除。