PARP-1 activity (PAR) determines the sensitivity of cervical cancer to olaparib.
Adult
Animals
Apoptosis
/ drug effects
Cell Growth Processes
/ drug effects
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Female
G2 Phase Cell Cycle Checkpoints
/ drug effects
Humans
M Phase Cell Cycle Checkpoints
/ drug effects
Mice, SCID
Middle Aged
Phthalazines
/ pharmacology
Piperazines
/ pharmacology
Poly (ADP-Ribose) Polymerase-1
/ metabolism
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Uterine Cervical Neoplasms
/ drug therapy
Xenograft Model Antitumor Assays
Young Adult
Cervical cancer
Olaparib
PAR
PARP
Journal
Gynecologic oncology
ISSN: 1095-6859
Titre abrégé: Gynecol Oncol
Pays: United States
ID NLM: 0365304
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
23
02
2019
revised:
06
08
2019
accepted:
08
08
2019
pubmed:
23
8
2019
medline:
7
11
2019
entrez:
23
8
2019
Statut:
ppublish
Résumé
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. 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. 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 IC 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.
Identifiants
pubmed: 31434613
pii: S0090-8258(19)31461-1
doi: 10.1016/j.ygyno.2019.08.010
pmc: PMC6788971
mid: NIHMS1537725
pii:
doi:
Substances chimiques
Phthalazines
0
Piperazines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
PARP1 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
olaparib
WOH1JD9AR8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
144-150Subventions
Organisme : NIH HHS
ID : S10 OD018521
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA176067
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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