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

Autor:	Dyshlovoy SA; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany.; Laboratory of Biologically Active Compounds, Institute of Science-Intensive Technologies and Advanced Materials, Far Eastern Federal University, Vladivostok 690922, Russian Federation., Hauschild J; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Venz S; Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald 17489, Germany.; Interfacultary Institute of Genetics and Functional Genomics, Department of Functional Genomics, University of Greifswald, Greifswald 17489, Germany., Krisp C; Section / Core Facility Mass Spectrometric Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Kolbe K; Laboratory for Brain Tumor Research, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Zapf S; Laboratory for Brain Tumor Research, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Heinemann S; Laboratory for Brain Tumor Research, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Fita KD; Laboratory for Brain Tumor Research, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Shubina LK; G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok 690022, Russian Federation., Makarieva TN; G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok 690022, Russian Federation., Guzii AG; G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok 690022, Russian Federation., Rohlfing T; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Kaune M; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Busenbender T; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Mair T; Section / Core Facility Mass Spectrometric Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Moritz M; Section / Core Facility Mass Spectrometric Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Poverennaya EV; Laboratory of Proteoform Interactomics, Institute of Biomedical Chemistry, Moscow 119121, Russian Federation., Schlüter H; Section / Core Facility Mass Spectrometric Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Serdyuk V; Zentrum für Molekulare Neurobiologie (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Stonik VA; G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok 690022, Russian Federation., Dierlamm J; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Bokemeyer C; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Mohme M; Laboratory for Brain Tumor Research, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Westphal M; Laboratory for Brain Tumor Research, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., Lamszus K; Laboratory for Brain Tumor Research, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany., von Amsberg G; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany.; Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg 20251, Germany., Maire CL; Laboratory for Brain Tumor Research, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany.
Jazyk:	angličtina
Zdroj:	Molecular pharmaceutics [Mol Pharm] 2023 Oct 02; Vol. 20 (10), pp. 4994-5005. Date of Electronic Publication: 2023 Sep 21.
DOI:	10.1021/acs.molpharmaceut.3c00217
Abstrakt:	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.
Databáze:	MEDLINE
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