2. Academic Validation
  3. Uncovering cellular senescence as a therapeutic target in NF2-related vestibular schwannoma

Uncovering cellular senescence as a therapeutic target in NF2-related vestibular schwannoma

  • Hear Res. 2025 Jan:455:109165. doi: 10.1016/j.heares.2024.109165.
Sandra Franco-Caspueñas 1,  Carmen García-Montoya 2,  Julio Contreras 3,  Luis Lassaletta 4,  Isabel Varela-Nieto 1,  Ana M Jiménez-Lara 5
Affiliations

Affiliations

  • 1 Neuropathology of Hearing and Myelinopathies Group. Institute for Biomedical Research Sols-Morreale, Spanish National Research Council, Autonomous University of Madrid (CSIC-UAM), 28029 Madrid, Spain; Rare Disease Network Biomedical Research Centre (CIBERER), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain; Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain.
  • 2 Neuropathology of Hearing and Myelinopathies Group. Institute for Biomedical Research Sols-Morreale, Spanish National Research Council, Autonomous University of Madrid (CSIC-UAM), 28029 Madrid, Spain; Rare Disease Network Biomedical Research Centre (CIBERER), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain.
  • 3 Neuropathology of Hearing and Myelinopathies Group. Institute for Biomedical Research Sols-Morreale, Spanish National Research Council, Autonomous University of Madrid (CSIC-UAM), 28029 Madrid, Spain; Rare Disease Network Biomedical Research Centre (CIBERER), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain; Department of Anatomy, School of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain.
  • 4 Rare Disease Network Biomedical Research Centre (CIBERER), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain; Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain; Department of Otorhinolaryngology, La Paz University Hospital, 28046 Madrid, Spain.
  • 5 Neuropathology of Hearing and Myelinopathies Group. Institute for Biomedical Research Sols-Morreale, Spanish National Research Council, Autonomous University of Madrid (CSIC-UAM), 28029 Madrid, Spain; Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain. Electronic address: amjimenez@iib.uam.es.
PMID: 39647233 DOI: 10.1016/j.heares.2024.109165
Abstract

Background: Vestibular schwannomas (VS) are complex and heterogeneous human tumors arising from the Schwann cell compartment of the vestibulocochlear nerve. VS cause significant neurological deficit such as hearing loss and vestibular impairment, and in some cases death due to brainstem compression. There is an urgent need to find pharmacotherapies for VS since surgical removal and stereotactic radiosurgery are the only effective treatments. Cancer therapy based in the combination of drug-induced senescence and senolytics may provide an innovative pharmacological alternative for VS management.

Methods: Senescence-associated β-galactosidase (SA-β-GAL) activity detection assay, real-time polymerase chain reaction (RT-PCR), western blotting and immunofluorescence, together with viability assays were used to analyze the response to different chemotherapy drugs of the human VS HEI-193 cell line. Human VS tumor paraffin sections were also studied for SA-β-GAL-stained cells.

Results: We found that chemotherapy compounds induced genotoxic stress and cellular senescence in HEI-193 VS cells, as characterized by increased SA-β-GAL activity, growth arrest, increased levels of the cyclin-dependent kinase inhibitor p21 and the accumulation of DNA damage. These cellular senescence markers were also accompanied by an increase of senescence-associated secretory phenotype (SASP): IL6, IL8, IL1B and MMP1. Induction of senescence by chemotherapy rendered HEI-193 VS cells as druggable targets for senolytic compounds, as navitoclax. Thus, treatment with navitoclax selectively eliminated bleomycin-induced senescent HEI-193 VS cells by activating the extrinsic and intrinsic Apoptosis pathways. Our data also show the presence of senescent cells, SA-β-GAL-positive stain, in human VS tumors, which are not present in healthy great auricular nerve sections.

Conclusions: These findings suggest that a one-two punch strategy of pro-senescence therapy induced by chemotherapy treatment followed by senolytic therapy represents a new paradigm for the pharmacological treatment of VS.

Keywords

Apoptosis; DNA damage; Genotoxic drugs; SASP; Senolysis; p21.

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