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Senolytic Targeting of Bcl-2 Anti-Apoptotic Family Increases Cell Death in Irradiated Sarcoma Cells

Lafontaine, Julie, Cardin, Guillaume B., Malaquin, Nicolas, Boisvert, Jean-Sébastien, Rodier, Francis, Wong, Philip·2021·Cancers
DOI 10.3390/cancers13030386PMC PMC7866159
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Abstract

Radiotherapy (RT) is a key component of cancer treatment. Most of the time, radiation is given after surgery but for soft-tissue sarcomas (STS), pre-surgical radiation is commonly utilized. However, despite improvements in RT accuracy, the rate of local recurrence remains high and is the major cause of death for patients with STS. A better understanding of cell fates in response to RT could provide new therapeutic options to enhance tumour cell killing by RT and facilitate surgical resection. Here, we showed that irradiated STS cell cultures do not die but instead undergo therapy-induced senescence (TIS), which is characterized by proliferation arrest, senescence-associated β-galactosidase activity, secretion of inflammatory cytokines and persistent DNA damage. STS-TIS was also associated with increased levels of the anti-apoptotic Bcl-2 family of proteins which rendered cells targetable using senolytic Bcl-2 inhibitors. As oppose to radiation alone, the addition of senolytic agents Venetoclax (ABT-199) or Navitoclax (ABT-263) after irradiation induced a rapid apoptotic cell death in STS monolayer cultures and in a more complex three-dimensional culture model. Together, these data suggest a new promising therapeutic approach for sarcoma patients who receive neoadjuvant RT. The addition of senolytic agents to radiation treatments may significantly reduce tumour volume prior to surgery and thereby improve the clinical outcome of patients.

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Metadata

Authors
Lafontaine, J., Cardin, G. B., Malaquin, N., Boisvert, J.-S., Rodier, F., & Wong, P.
Affiliations
Institut du Cancer de Montréal (ICM), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), 900 St. Denis Street, Montreal, QC H2X 0A9, Canada
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2021-01-21
Volume
13
Issue
3
Pages
386
ISSN
2072-6694
DOI
10.3390/cancers13030386
PMC
PMC7866159
Cited by
54
References
21
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Cancer Research Society (20276)
  • Fonds de Recherche du Québec – AUDACE (262832)

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