Combining inotuzumab ozogamicin with PARP inhibitors olaparib and talazoparib exerts synergistic cytotoxicity in acute lymphoblastic leukemia by inhibiting DNA strand break repair.
Oncol Rep
; 52(1)2024 Jul.
Article
de En
| MEDLINE
| ID: mdl-38785163
ABSTRACT
Inotuzumab ozogamicin (IO), a novel therapeutic drug for relapsed or refractory acute lymphoblastic leukemia (RR)(ALL), is a humanized anticluster of differentiation (CD) 22 monoclonal antibody conjugated with calicheamicin that causes DNA single and doublestrand breaks. Although the efficacy of IO is significantly improved compared with that of conventional chemotherapies, the prognosis for RRALL remains poor, highlighting the need for more effective treatment strategies. The present study examined the role of DNA damage repair inhibition using the poly (ADPribose) polymerase (PARP) inhibitors olaparib or talazoparib on the enhancement of the antitumor effects of IO on BALL cells in vitro. The Reh, Philadelphia (Ph)BALL and the SUPB15 Ph+ BALL cell lines were used for experiments. Both cell lines were ~90% CD22+. The halfmaximal inhibitory concentration (IC50) values of IO were 5.3 and 49.7 ng/ml for Reh and SUPB15 cells, respectively. The IC50 values of IO combined with minimally toxic concentrations of olaparib or talazoparib were 0.8 and 2.9 ng/ml for Reh cells, respectively, and 36.1 and 39.6 ng/ml for SUPB15 cells, respectively. The combination index of IO with olaparib and talazoparib were 0.19 and 0.56 for Reh cells and 0.76 and 0.89 for SUPB15 cells, demonstrating synergistic effects in all combinations. Moreover, the addition of minimally toxic concentrations of PARP inhibitors augmented IOinduced apoptosis. The alkaline comet assay, which quantitates the amount of DNA strand breaks, was used to investigate the degree to which DNA damage observed 1 h after IO administration was repaired 6 h later, reflecting successful repair of DNA strand breaks. However, DNA strand breaks persisted 6 h after IO administration combined with olaparib or talazoparib, suggesting inhibition of the repair processes by PARP inhibitors. Adding olaparib or talazoparib thus synergized the antitumor effects of IO by inhibiting DNA strand break repair via the inhibition of PARP.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Phtalazines
/
Pipérazines
/
Réparation de l'ADN
/
Synergie des médicaments
/
Leucémie-lymphome lymphoblastique à précurseurs B et T
/
Inhibiteurs de poly(ADP-ribose) polymérases
/
Inotuzumab ozogamicine
Limites:
Humans
Langue:
En
Journal:
Oncol Rep
/
Oncol. rep
/
Oncology reports
Sujet du journal:
NEOPLASIAS
Année:
2024
Type de document:
Article
Pays d'affiliation:
Japon
Pays de publication:
Grèce