Radiation-induced synthetic lethality: combination of poly(ADP-ribose) polymerase and RAD51 inhibitors to sensitize cells to proton irradiation.
Cell Cycle
; 18(15): 1770-1783, 2019 08.
Article
em En
| MEDLINE
| ID: mdl-31238782
ABSTRACT
Although improvements in radiation therapy were made over the years, radioresistance is still a major challenge. Cancer cells are often deficient for DNA repair response, a feature that is currently exploited as a new anti-cancer strategy. In this context, combination of inhibitors targeting complementary pathways is of interest to sensitize cells to radiation. In this work, we used PARP (Olaparib) and RAD51 (B02) inhibitors to radiosensitize cancer cells to proton and X-ray radiation. More particularly, Olaparib and B02 were used at concentration leading to limited cytotoxic (alone or in combination) but increasing cell death when the cells were irradiated. We showed that, although at limited concentration, Olaparib and B02 were able to radiosensitize different cancer cell lines, i.e. lung and pancreatic cancer cells. Antagonistic, additive or synergistic effects were observed and correlated to cell proliferation rate. The inhibitors enhanced persistent DNA damage, delayed apoptosis, prolonged cell cycle arrest and senescence upon irradiation. These results demonstrated that radiation-induced synthetic lethality might widen the therapeutic window, hence extending the use of PARP inhibitors to patients without BRCAness.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Radiossensibilizantes
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Rad51 Recombinase
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Inibidores de Poli(ADP-Ribose) Polimerases
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Mutações Sintéticas Letais
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Neoplasias
Idioma:
En
Revista:
Cell Cycle
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Bélgica