HSP90 inhibitor gedunin impairs glioblastoma proliferation and invasiveness

Costa, T. E. M. M.; Padua, T. A.; Pereira, J. X.; Rodrigues, V. G.; Seito, L. N.; Cunha, E. M.; Filgueiras, C. C.; Abreu-Villaca, Y.; Manhaes, A. C.; Maya-Monteiro, C. M.; Henriques, M. d. G.; Krahe, T. E.; Penido, C.

doi:10.1101/2023.06.02.543101

bioRxiv · 10.1101/2023.06.02.543101

HSP90 inhibitor gedunin impairs glioblastoma proliferation and invasiveness

Costa, T. E. M. M.·Padua, T. A.·Pereira, J. X.·Rodrigues, V. G.·Seito, L. N.·Cunha, E. M.·Filgueiras, C. C.·Abreu-Villaca, Y.·Manhaes, A. C.·Maya-Monteiro, C. M.·Henriques, M. d. G.·Krahe, T. E.·Penido, C.

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Abstract

BackgroundGlioblastoma is the most invasive and malignant brain tumor, for which no effective treatment is currently available. Heat shock protein 90 (HSP90) is a potential target for the treatment of different types of cancer. Herein, we investigated the effect of gedunin, an HSP90 inhibitor, in murine GL261 glioblastoma in vitro and in vivo models. MethodsGedunin effects were assessed by in vitro cell viability assay (MTT), apoptosis (PI/Annexin staining), proliferation (CFSE), invasion (transmigration, scratch assay and zymography), protein detection (western blot) and in vivo orthotopic glioblastoma model (brain computed tomography and histology). ResultsGedunin treatment decreased GL261 cell proliferation and triggered apoptosis in a concentration-dependent manner. Gedunin also reduced GL261 cell migration and metalloproteinase-2 activity, suggesting that it impairs glioblastoma cell invasion. Despite the reduction of total protein content in gedunin-treated cells, the phosphorylation of STAT3 and ERK1/2 pathways was enhanced within 24 h. In situ treatment with gedunin did not significantly reduce tumor volume. Still, it reduced the tumor central area and the presence of vascular structures in xenograft glioblastoma in C57BL/6 mice, a clinical feature associated with morbidity and mortality. ConclusionGedunin inhibits murine glioblastoma cell growth and proliferation by inducing apoptosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/543101v4_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@15ea03corg.highwire.dtl.DTLVardef@169e5b1org.highwire.dtl.DTLVardef@16705bdorg.highwire.dtl.DTLVardef@a9c74b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Costa, T. E. M. M., Padua, T. A., Pereira, J. X., Rodrigues, V. G., Seito, L. N., Cunha, E. M., Filgueiras, C. C., Abreu-Villaca, Y., Manhaes, A. C., Maya-Monteiro, C. M., Henriques, M. d. G., Krahe, T. E., Penido, C.. 2023-06-05. HSP90 inhibitor gedunin impairs glioblastoma proliferation and invasiveness. https://doi.org/10.1101/2023.06.02.543101

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