PARP-1 activity (PAR) determines the sensitivity of cervical cancer to olaparib.
Gynecol Oncol
; 155(1): 144-150, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31434613
ABSTRACT
OBJECTIVES:
Cervical cancer (CC) remains a major health problem worldwide. Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutics in ovarian cancer. We explored the preclinical in vitro and in vivo activity of olaparib against multiple primary whole exome sequenced (WES) CC cells lines and xenografts.METHODS:
Olaparib cell-cycle, apoptosis, homologous-recombination-deficiency (HRD), PARP trapping and cytotoxicity activity was evaluated against 9 primary CC cell lines in vitro. PARP and PAR expression were analyzed by Western blot assays. Finally, olaparib in vivo antitumor activity was tested against CC xenografts.RESULTS:
While none of the cell lines demonstrated HRD, three out of 9 (33.3%) primary CC cell lines showed strong PARylation activity and demonstrated high sensitivity to olaparib in vitro treatment (cutoff IC50 valuesâ¯<â¯2⯵M, pâ¯=â¯0.0012). Olaparib suppressed CC cell growth through cell cycle arrest in the G2/M phase and caused apoptosis (pâ¯<â¯0.0001). Olaparib activity in CC involved both PARP enzyme inhibition and trapping. In vivo, olaparib significantly impaired CC xenografts tumor growth (pâ¯=â¯0.0017) and increased overall animal survival (pâ¯=â¯0.008).CONCLUSIONS:
A subset of CC primary cell lines is highly responsive to olaparib treatment in vitro and in vivo. High level of PARylation correlated with olaparib preclinical activity and may represent a useful biomarker for the identification of CC patients benefitting the most from PARPi.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ftalazinas
/
Piperazinas
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Neoplasias do Colo do Útero
/
Inibidores de Poli(ADP-Ribose) Polimerases
/
Poli(ADP-Ribose) Polimerase-1
Tipo de estudo:
Diagnostic_studies
Limite:
Adult
/
Animals
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Female
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Humans
/
Middle aged
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article