The Temozolomide-Doxorubicin paradox in Glioblastoma in vitro-in silico preclinical drug-screening.

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dc.creatorOraiopoulou, Mariam-Eleni
dc.creatorTzamali, Eleftheria
dc.creatorPsycharakis, Stylianos E
dc.creatorTzedakis, Georgios
dc.creatorMakatounakis, Takis
dc.creatorManolitsi, Katina
dc.creatorDrakos, Elias
dc.creatorVakis, Antonis F
dc.creatorZacharakis, Giannis
dc.creatorPapamatheakis, Joseph
dc.creatorSakkalis, Vangelis
dc.date2024-02-14T16:18:37Z
dc.date2024-02-14
dc.date2023-07-25
dc.date2024-02-14T16:18:36Z
dc.date.accessioned2026-08-03T03:48:07Z
dc.descriptionAcknowledgements: Authors would like to thank Eleftheria Parasiraki, Evangelos Liapis for all the help they provided, as well as Despina Tsoukatou for the expert technical assistance.
dc.descriptionAdjuvant Temozolomide is considered the front-line Glioblastoma chemotherapeutic treatment; yet not all patients respond. Latest trends in clinical trials usually refer to Doxorubicin; yet it can lead to severe side-effects if administered in high doses. While Glioblastoma prognosis remains poor, little is known about the combination of the two chemotherapeutics. Patient-derived spheroids were generated and treated with a range of Temozolomide/Doxorubicin concentrations either as monotherapy or in combination. Optical microscopy was used to monitor the growth pattern and cell death. Based on the monotherapy experiments, we developed a probabilistic mathematical framework in order to describe the drug-induced effect at the single-cell level and simulate drug doses in combination assuming probabilistic independence. Doxorubicin was found to be effective in doses even four orders of magnitude less than Temozolomide in monotherapy. The combination therapy doses tested in vitro were able to lead to irreversible growth inhibition at doses where monotherapy resulted in relapse. In our simulations, we assumed both drugs are anti-mitotic; Temozolomide has a growth-arrest effect, while Doxorubicin is able to cumulatively cause necrosis. Interestingly, under no mechanistic synergy assumption, the in silico predictions underestimate the in vitro results. In silico models allow the exploration of a variety of potential underlying hypotheses. The simulated-biological discrepancy at certain doses indicates a supra-additive response when both drugs are combined. Our results suggest a Temozolomide-Doxorubicin dual chemotherapeutic scheme to both disable proliferation and increase cytotoxicity against Glioblastoma.
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dc.identifier2045-2322
dc.identifiers41598-024-53684-y
dc.identifier53684
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/364571
dc.identifier2045-2322
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/180899
dc.languageen
dc.languageeng
dc.publisherSpringer Nature
dc.publisherhttps://doi.org/10.1038/s41598-024-53684-y
dc.rightsAttribution 4.0 International
dc.rightshttp://creativecommons.org/licenses/by/4.0/
dc.subjectBrain cancer
dc.subjectComputational models
dc.subjectDoxorubicin
dc.subjectPreclinical drug-screening
dc.subjectTemozolomide
dc.subjectHumans
dc.subjectTemozolomide
dc.subjectGlioblastoma
dc.subjectCell Line, Tumor
dc.subjectNeoplasm Recurrence, Local
dc.subjectDoxorubicin
dc.subjectBrain Neoplasms
dc.titleThe Temozolomide-Doxorubicin paradox in Glioblastoma in vitro-in silico preclinical drug-screening.
dc.typeArticle

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