Sequential Treatment with Temozolomide Plus Naturally Derived AT101 as an Alternative Therapeutic Strategy: Insights into Chemoresistance Mechanisms of Surviving Glioblastoma Cells

Autor:	Dana Hellmold, Carolin Kubelt, Tina Daunke, Silje Beckinger, Ottmar Janssen, Margarethe Hauck, Fabian Schütt, Rainer Adelung, Ralph Lucius, Jochen Haag, Susanne Sebens, Michael Synowitz, Janka Held-Feindt
Jazyk:	angličtina
Rok vydání:	2023
Předmět:	Inorganic Chemistry glioblastoma R-(-)-gossypol AT101 temozolomide chemoresistance combined therapy mTOR stemness epithelial–mesenchymal transition Organic Chemistry General Medicine Physical and Theoretical Chemistry Molecular Biology Spectroscopy Catalysis Computer Science Applications
Zdroj:	International Journal of Molecular Sciences; Volume 24; Issue 10; Pages: 9075
ISSN:	1422-0067
DOI:	10.3390/ijms24109075
Popis:	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.
Databáze:	OpenAIRE
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