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Peer-reviewedCC BY 4.0Frontiers in Neuroscience

Three-dimensional in vitro models for assessing temozolomide sensitivity in glioblastoma

  • Andresa Hiromi Sakai1
  • Marna Eliana Sakalem2
  • Luiza Magosso Oliveira Rocha1
  • Isabely Mayara da Silva1
  • Flávia Eliza Staut Silva1
  • Diego Luís Ribeiro3
  • Carlos Frederico Martins Menck3
  • Helber Alves Negreiros4
  • João Marcelo de Castro e Sousa5
  • Juliana Mara Serpeloni1
5 affiliations
  1. 1Department of General Biology, Center of Biological Sciences, State University of Londrina (UEL)
  2. 2Department of Anatomy, Center of Biological Sciences, State University of Londrina (UEL)
  3. 3Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (ICB/USP)
  4. 4Postgraduate Program in Pharmaceutical Sciences, Toxicological Genetics Research Laboratory, Federal University of Piauí
  5. 5Toxicological Genetics Research Laboratory (Lapgenic), Center for Heath of Sciences, Federal University of Piaui
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Abstract

IDH-wildtype glioblastoma, or glioblastoma multiforme (GBM), is the most aggressive primary malignancy of the central nervous system. It is characterized by marked invasiveness, intratumoral heterogeneity, and high recurrence rates, largely driven by intrinsic and acquired resistance to standard temozolomide (TMZ) therapy. TMZ is an oral alkylating agent that methylates nitrogenous bases, mainly forming O ⁶ -methylguanine (O ⁶ -meG) lesions, the main cytotoxic and mutagenic events responsible for its antitumor effects. This review first characterizes gliomas and the mechanism of action of the main GBM treatment drug (TMZ), then critically examines in vitro cell culture models investigating these mechanisms. This review emphasizes the development and application of three-dimensional (3D) culture systems, including tumor spheroids and organoids, which more effectively recapitulate tumor architecture, cell–cell interactions, and drug penetration gradients than conventional two-dimensional models. This review discusses the strengths and limitations of these models and their translational relevance to modeling TMZ sensitivity and resistance in GBM.

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Cite

BibTeXRIS
BibTeX
@article{sakai2026threedimensional,
  title = {{Three-dimensional in vitro models for assessing temozolomide sensitivity in glioblastoma}},
  author = {Andresa Hiromi Sakai and Marna Eliana Sakalem and Luiza Magosso Oliveira Rocha and Isabely Mayara da Silva and Flávia Eliza Staut Silva and Diego Luís Ribeiro and Carlos Frederico Martins Menck and Helber Alves Negreiros and João Marcelo de Castro e Sousa and Juliana Mara Serpeloni},
  journal = {Frontiers in Neuroscience},
  year = {2026},
  month = oct,
  doi = {10.3389/fnins.2026.1901494},
  url = {https://www.frontiersin.org/articles/10.3389/fnins.2026.1901494/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Three-dimensional in vitro models for assessing temozolomide sensitivity in glioblastoma
AU  - Andresa Hiromi Sakai
AU  - Marna Eliana Sakalem
AU  - Luiza Magosso Oliveira Rocha
AU  - Isabely Mayara da Silva
AU  - Flávia Eliza Staut Silva
AU  - Diego Luís Ribeiro
AU  - Carlos Frederico Martins Menck
AU  - Helber Alves Negreiros
AU  - João Marcelo de Castro e Sousa
AU  - Juliana Mara Serpeloni
PY  - 2026
DA  - 2026/10/21
JO  - Frontiers in Neuroscience
DO  - 10.3389/fnins.2026.1901494
UR  - https://www.frontiersin.org/articles/10.3389/fnins.2026.1901494/full
AB  - IDH-wildtype glioblastoma, or glioblastoma multiforme (GBM), is the most aggressive primary malignancy of the central nervous system. It is characterized by marked invasiveness, intratumoral heterogeneity, and high recurrence rates, largely driven by intrinsic and acquired resistance to standard temozolomide (TMZ) therapy. TMZ is an oral alkylating agent that methylates nitrogenous bases, mainly forming O ⁶ -methylguanine (O ⁶ -meG) lesions, the main cytotoxic and mutagenic events responsible for its antitumor effects. This review first characterizes gliomas and the mechanism of action of the main GBM treatment drug (TMZ), then critically examines in vitro cell culture models investigating these mechanisms. This review emphasizes the development and application of three-dimensional (3D) culture systems, including tumor spheroids and organoids, which more effectively recapitulate tumor architecture, cell–cell interactions, and drug penetration gradients than conventional two-dimensional models. This review discusses the strengths and limitations of these models and their translational relevance to modeling TMZ sensitivity and resistance in GBM.
SN  - 1662-453X
SN  - 1662-4548
ER  -