Cytotoxicity and Differentiating Effect of the Poly(ADP-Ribose) Polymerase Inhibitor Olaparib in Myelodysplastic Syndromes

Cancers

Emiliano Fabiani¹  Francesco Lo-Coco¹  MariaTeresa Voso¹  Giulia Falconi¹  MariaIrno Consalvo¹  Ambra Di Veroli¹  Luca Maurillo²  Paola Curzi²  Pasquale Niscola³  Manuela Giansanti⁴  Isabella Faraoni⁴  Lucio Tentori⁴  Francesca Aloisio⁴  Francesca Di Cristino⁴  Grazia Graziani⁴ 

[1] Hematology Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy;Hematology Unit, Tor Vergata Hospital, 00133 Rome, Italy;Hematology Unit, “S. Eugenio” Hospital, 00144 Rome, Italy;Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;

关键词: MDS;    PARP inhibitors;    olaparib;    hematopoietic differentiation;    PARP1;    AML;   

DOI  :  10.3390/cancers11091373

来源: DOAJ

【 摘 要 】

Myelodysplastic syndromes (MDS) are highly heterogeneous myeloid diseases, characterized by frequent genetic/chromosomal aberrations. Olaparib is a potent, orally bioavailable poly(ADP-ribose) polymerase 1 (PARP1) inhibitor with acceptable toxicity profile, designed as targeted therapy for DNA repair defective tumors. Here, we investigated olaparib activity in primary cultures of bone marrow mononuclear cells collected from patients with MDS (n = 28). A single treatment with olaparib induced cytotoxic effects in most samples, with median IC₅₀ of 5.4 µM (2.0−24.8 µM), lower than plasma peak concentration reached in vivo. In addition, olaparib induced DNA damage as shown by a high proportion of γH2AX positive cells in samples with low IC₅₀s. Olaparib preferentially killed myeloid cells causing a significant reduction of blasts and promyelocytes, paralleled by an increase in metamyelocytes and mature granulocytes while sparing lymphocytes that are not part of the MDS clone. Consistently, flow cytometry analysis revealed a decrease of CD117+/CD123+ immature progenitors (p < 0.001) and induction of CD11b+/CD16+ (p < 0.001) and CD10+/CD15+ (p < 0.01) neutrophils. Morphological and immunophenotypic changes were associated with a dose-dependent increase of PU.1 and CEBPA transcription factors, which are drivers of granulocytic and monocytic differentiation. Moreover, the combination of olaparib with decitabine resulted in augmented cytotoxic and differentiating effects. Our data suggest that olaparib may have therapeutic potential in MDS patients.

【 授权许可】

Unknown