| Autor: |
Lafontaine J; 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., Cardin GB; 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., Malaquin N; 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., Boisvert JS; 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.; Plasma Processing Laboratory, Department of Chemical Engineering, McGill University, 3610 University Street, Montreal, QC H3A 0C5, Canada., Rodier F; 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.; Département de Radiologie, Radio-Oncologie et Médicine Nucléaire, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, QC H3C 3J7, Canada., Wong P; 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.; Département de Radio-Oncologie, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Sanguinet Street, Montreal, QC H2X 3E4, Canada.; Department of Radiation Oncology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON M5G 2M9, Canada.; Department of Radiation Oncology, University of Toronto, 149 College Street, Suite 504, Toronto, ON M5T 1P5, Canada. |
| Abstrakt: |
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. |
