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Sequential Treatment with Temozolomide Plus Naturally Derived AT101 as an Alternative Therapeutic Strategy: Insights into Chemoresistance Mechanisms of Surviving Glioblastoma Cells.
Hellmold, Dana; Kubelt, Carolin; Daunke, Tina; Beckinger, Silje; Janssen, Ottmar; Hauck, Margarethe; Schütt, Fabian; Adelung, Rainer; Lucius, Ralph; Haag, Jochen; Sebens, Susanne; Synowitz, Michael; Held-Feindt, Janka.
Afiliación
  • Hellmold D; Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.
  • Kubelt C; Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.
  • Daunke T; Institute of Experimental Cancer Research, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.
  • Beckinger S; Institute of Experimental Cancer Research, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.
  • Janssen O; Institute for Immunology, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.
  • Hauck M; Functional Nanomaterials, Department of Materials Science, Kiel University, 24143 Kiel, Germany.
  • Schütt F; Functional Nanomaterials, Department of Materials Science, Kiel University, 24143 Kiel, Germany.
  • Adelung R; Functional Nanomaterials, Department of Materials Science, Kiel University, 24143 Kiel, Germany.
  • Lucius R; Institute of Anatomy, Kiel University, 24098 Kiel, Germany.
  • Haag J; Department of Pathology, Kiel University, 24105 Kiel, Germany.
  • Sebens S; Institute of Experimental Cancer Research, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.
  • Synowitz M; Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.
  • Held-Feindt J; Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.
Int J Mol Sci ; 24(10)2023 May 22.
Article en En | MEDLINE | ID: mdl-37240419
Glioblastoma (GBM) is a poorly treatable disease due to the fast development of tumor recurrences and high resistance to chemo- and radiotherapy. To overcome the highly adaptive behavior of GBMs, especially multimodal therapeutic approaches also including natural adjuvants have been investigated. However, despite increased efficiency, some GBM cells are still able to survive these advanced treatment regimens. Given this, the present study evaluates representative chemoresistance mechanisms of surviving human GBM primary cells in a complex in vitro co-culture model upon sequential application of temozolomide (TMZ) combined with AT101, the R(-) enantiomer of the naturally occurring cottonseed-derived gossypol. Treatment with TMZ+AT101/AT101, although highly efficient, yielded a predominance of phosphatidylserine-positive GBM cells over time. Analysis of the intracellular effects revealed phosphorylation of AKT, mTOR, and GSK3ß, resulting in the induction of various pro-tumorigenic genes in surviving GBM cells. A Torin2-mediated mTOR inhibition combined with TMZ+AT101/AT101 partly counteracted the observed TMZ+AT101/AT101-associated effects. Interestingly, treatment with TMZ+AT101/AT101 concomitantly changed the amount and composition of extracellular vesicles released from surviving GBM cells. Taken together, our analyses revealed that even when chemotherapeutic agents with different effector mechanisms are combined, a variety of chemoresistance mechanisms of surviving GBM cells must be taken into account.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Gosipol / Glioblastoma Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Gosipol / Glioblastoma Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Suiza