Rhizochalinin在体外模型中展示出抗癌活性，并且与EGFR抑制剂协同作用于胶质母细胞瘤。
Rhizochalinin Exhibits Anticancer Activity and Synergizes with EGFR Inhibitors in Glioblastoma In Vitro Models.
发表日期：2023 Sep 21
作者：
Sergey A Dyshlovoy, Jessica Hauschild, Simone Venz, Christoph Krisp, Katharina Kolbe, Svenja Zapf, Sarina Heinemann, Krystian D Fita, Larisa K Shubina, Tatyana N Makarieva, Alla G Guzii, Tina Rohlfing, Moritz Kaune, Tobias Busenbender, Thomas Mair, Manuela Moritz, Ekaterina V Poverennaya, Hartmut Schlüter, Volodymyr Serdyuk, Valentin A Stonik, Judith Dierlamm, Carsten Bokemeyer, Malte Mohme, Manfred Westphal, Katrin Lamszus, Gunhild von Amsberg, Cecile L Maire
来源：
Stem Cell Research & Therapy
摘要：
Rhizochalinin（简称Rhiz）是从海洋天然化合物rhizochalin合成的一种新发现的细胞毒性鞘磷脂。之前，Rhiz在各种癌症模型中的体外和体内有效性得到了高度证明。在这里，我们报道了Rhiz在人类胶质母细胞瘤细胞系以及患者来源的胶质母细胞瘤干细胞样神经球模型中具有极高的活性。Rhiz通过诱导凋亡、G2/M期细胞周期阻滞和抑制自噬来对抗胶质母细胞瘤细胞的增殖。蛋白质组学分析和生物信息学分析表明，Rhiz的一个主要生物学效应可能是抑制Akt信号通路。Rhiz处理后，Akt、IGF-1R和MEK1/2激酶的抑制也得到了验证。此外，Rhiz预处理使患者来源的胶质瘤球对γ-射线治疗的抑制作用更加显著，其中Akt的抑制可能也起到了决定性的贡献作用。相反，在Rhiz处理下，观察到所有胶质母细胞瘤神经球中均发现EGFR上调，被认为可能是初期耐药的一个可能迹象。与此一致的是，与EGFR靶向酪氨酸激酶抑制剂联合治疗可以显著增强Rhiz的疗效，导致胶质母细胞瘤细胞存活率显著抑制，同时与拉帕替尼联合治疗还可以显著减小神经球的大小。首次的体外数据表明，Rhiz不能穿过血脑屏障，因此在进一步的体内研究中应该使用其他药物输送方法。总之，Rhiz是治疗人类胶质母细胞瘤的有希望的新候选药物，应该与EGFR抑制剂联合开发。
Rhizochalinin (Rhiz) is a recently discovered cytotoxic sphingolipid synthesized from the marine natural compound rhizochalin. Previously, Rhiz demonstrated high in vitro and in vivo efficacy in various cancer models. Here, we report Rhiz to be highly active in human glioblastoma cell lines as well as in patient-derived glioma-stem like neurosphere models. Rhiz counteracted glioblastoma cell proliferation by inducing apoptosis, G2/M-phase cell cycle arrest, and inhibition of autophagy. Proteomic profiling followed by bioinformatic analysis suggested suppression of the Akt pathway as one of the major biological effects of Rhiz. Suppression of Akt as well as IGF-1R and MEK1/2 kinase was confirmed in Rhiz-treated GBM cells. In addition, Rhiz pretreatment resulted in a more pronounced inhibitory effect of γ-irradiation on the growth of patient-derived glioma-spheres, an effect to which the Akt inhibition may also contribute decisively. In contrast, EGFR upregulation, observed in all GBM neurospheres under Rhiz treatment, was postulated to be a possible sign of incipient resistance. In line with this, combinational therapy with EGFR-targeted tyrosine kinase inhibitors synergistically increased the efficacy of Rhiz resulting in dramatic inhibition of GBM cell viability as well as a significant reduction of neurosphere size in the case of combination with lapatinib. Preliminary in vitro data generated using a parallel artificial membrane permeability (PAMPA) assay suggested that Rhiz cannot cross the blood brain barrier and therefore alternative drug delivery methods should be used in the further in vivo studies. In conclusion, Rhiz is a promising new candidate for the treatment of human glioblastoma, which should be further developed in combination with EGFR inhibitors.