2. Academic Validation
  3. HDAC6 inhibition through WT161 synergizes with temozolomide, induces apoptosis, reduces cell motility, and decreases β-catenin levels in glioblastoma cells

HDAC6 inhibition through WT161 synergizes with temozolomide, induces apoptosis, reduces cell motility, and decreases β-catenin levels in glioblastoma cells

  • Invest New Drugs. 2025 Feb 15. doi: 10.1007/s10637-025-01508-9.
Leilane Sales Oliveira 1 2,  João Marcos Oliveira-Silva 1 2,  Hebreia Oliveira Almeida-Souza 3,  Mario Machado Martins 3,  Carolina Berraut Chiminazo 1,  Rafael Fonseca 4,  Carlos Vinicius Expedito de Souza 1,  Alexandre Ferro Aissa 5 2,  Luciana Machado Bastos 3,  Marisa Ionta 4,  Graziela Domingues de Almeida Lima 4 2,  Angel Mauricio Castro-Gamero 6 7
Affiliations

Affiliations

  • 1 Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
  • 2 Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
  • 3 Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38400-902, Brazil.
  • 4 Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
  • 5 Division of Genetics, Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil.
  • 6 Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil. mauricio.castro@unifal-mg.edu.br.
  • 7 Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil. mauricio.castro@unifal-mg.edu.br.
PMID: 39954199 DOI: 10.1007/s10637-025-01508-9
Abstract

Glioblastoma multiforme (GBM) accounts for 70% of all primary malignancies of the central nervous system. Current treatment strategies involve surgery followed by chemotherapy with temozolomide (TMZ); however, the median survival after treatment is approximately 15 months. Many GBM cases develop resistance to TMZ, resulting in a poor prognosis for patients, which underscores the urgent need for novel therapeutic approaches. One promising avenue is the inhibition of histone deacetylase 6 (HDAC6), an Enzyme that deacetylates α-tubulin and is increasingly recognized as a potential pharmacological target in Cancer. In GBM specifically, HDAC6 overexpression has been linked to poor prognosis and chemoresistance. In this study, we demonstrate that HDAC6 protein levels are elevated in GBM and evaluate the effects of the novel selective HDAC6 Inhibitor, WT161, on U251, U87, and T98G cells to assess its potential to revert the malignant phenotype. Our results show a significant increase in acetylated α-tubulin levels, suppression of cell growth, cell cycle arrest at the G2/M phase, and decreased clonogenicity of 2D-cultured GBM cells. Additionally, WT161 acted synergistically with TMZ, induced Apoptosis and enhanced TMZ-induced Apoptosis. Notably, HDAC6 inhibition resulted in reduced cell migration and invasion, associated with decreased β-catenin levels. When cultured in 3D conditions, WT161-treated T98G spheroids were sensitized to TMZ and exhibited reduced migration. Finally, HDAC6 inhibition altered the metabolome, particularly affecting metabolites associated with lipid peroxidation. In conclusion, our data reveal, for the first time, the efficacy of the selective HDAC6 Inhibitor WT161 in a preclinical GBM setting.

Keywords

Glioblastoma; HDAC6 inhibition; Metabolome; TMZ resistance; Tumor progression.

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