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The Warburg Trap: a novel therapeutic approach for targeting osteosarcoma

Although urgently needed, no significant improvements in osteosarcoma (OS) therapy have been achieved within the last decades. Here, we present a new therapeutic approach based on drug combinations consisting of mitochondrial complex I (MCI) inhibitors and ionophores that induce cancer cell-specific...

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Hauptverfasser: Fellenberg, Jörg (VerfasserIn) , Losch, Sarina (VerfasserIn) , Tripel, Elena (VerfasserIn) , Lehner, Burkhard (VerfasserIn) , Melnik, Svitlana (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2024
In: Cells
Year: 2024, Jahrgang: 13, Heft: 1, Pages: 1-17
ISSN:2073-4409
DOI:10.3390/cells13010061
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cells13010061
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2073-4409/13/1/61
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Verfasserangaben:Joerg Fellenberg, Sarina Losch, Elena Tripel, Burkhard Lehner and Svitlana Melnik

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520 |a Although urgently needed, no significant improvements in osteosarcoma (OS) therapy have been achieved within the last decades. Here, we present a new therapeutic approach based on drug combinations consisting of mitochondrial complex I (MCI) inhibitors and ionophores that induce cancer cell-specific cell death based on a modulation of cellular energy metabolism and intracellular pH (pHi) named the Warburg Trap (WT). The effects of several drug combinations on intracellular pH, cell viability, colony-forming capacity and expression of WNT-target genes were analysed using OS cell lines and primary human osteoblasts (HOB). Tumour take rates and tumour volumes were analysed in vivo using a chicken chorioallantoic membrane assay (CAM). Several WT drug combinations induced the intracellular acidification and apoptotic cell death in OS cells, whereas HOBs tolerated the treatment. A significant inhibition of the colony-forming ability of OS cells and downregulation of WNT-target genes suggest that cancer stem cells (CSCs) are also targeted by the WT approach. In vivo, we observed a significant reduction in the tumour take rates in response to WT drug treatment. Our data suggest that the Warburg Trap is a promising approach for the development of a novel and effective OS therapy to replace or supplement the current OS chemotherapy. 
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