Rhizochalinin Exhibits Anticancer Activity and Synergizes with EGFR Inhibitors in Glioblastoma In Vitro Models

拉帕蒂尼 神经球 蛋白激酶B 胶质瘤 癌症研究 PI3K/AKT/mTOR通路 体内 酪氨酸激酶 细胞生长 化学 生物 体外 细胞凋亡 药理学 信号转导 细胞生物学 癌症 生物化学 曲妥珠单抗 乳腺癌 内皮干细胞 遗传学 生物技术 成体干细胞
作者
Sergey A. Dyshlovoy,Jessica Hauschild,Simone Venz,Christoph Krisp,Katharina Kolbe,Svenja Zapf,Sarina Heinemann,Krystian 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
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
卷期号:20 (10): 4994-5005 被引量:4
标识
DOI:10.1021/acs.molpharmaceut.3c00217
摘要

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.
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