Combining inotuzumab ozogamicin with PARP inhibitors olaparib and talazoparib exerts synergistic cytotoxicity in acute lymphoblastic leukemia by inhibiting DNA strand break repair

Ida,Naoko; Okura,Miyuki; Tanaka,Saki; Hosono,Naoko; Yamauchi,Takahiro

doi:10.3892/or.2024.8749

Combining inotuzumab ozogamicin with PARP inhibitors olaparib and talazoparib exerts synergistic cytotoxicity in acute lymphoblastic leukemia by inhibiting DNA strand break repair

Authors:
- Naoko Ida
- Miyuki Okura
- Saki Tanaka
- Naoko Hosono
- Takahiro Yamauchi
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Affiliations: Department of Hematology and Oncology, University of Fukui, Matsuoka, Eiheiji, Fukui 910‑1193, Japan, Department of Blood Transfusion, University of Fukui Hospital, Matsuoka, Eiheiji, Fukui 910‑1193, Japan
Published online on: May 21, 2024 https://doi.org/10.3892/or.2024.8749
Article Number: 90

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Abstract

Inotuzumab ozogamicin (IO), a novel therapeutic drug for relapsed or refractory acute lymphoblastic leukemia (RR)‑(ALL), is a humanized anti‑cluster of differentiation (CD) 22 monoclonal antibody conjugated with calicheamicin that causes DNA single‑ and double‑strand breaks. Although the efficacy of IO is significantly improved compared with that of conventional chemotherapies, the prognosis for RR‑ALL remains poor, highlighting the need for more effective treatment strategies. The present study examined the role of DNA damage repair inhibition using the poly (ADP‑ribose) polymerase (PARP) inhibitors olaparib or talazoparib on the enhancement of the antitumor effects of IO on B‑ALL cells in vitro. The Reh, Philadelphia (Ph)^‑B‑ALL and the SUP‑B15 Ph⁺ B‑ALL cell lines were used for experiments. Both cell lines were ~90% CD22⁺. The half‑maximal inhibitory concentration (IC₅₀) values of IO were 5.3 and 49.7 ng/ml for Reh and SUP‑B15 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 SUP‑B15 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 SUP‑B15 cells, demonstrating synergistic effects in all combinations. Moreover, the addition of minimally toxic concentrations of PARP inhibitors augmented IO‑induced 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.

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