Cancers, Vol. 11, Pages 1373: Cytotoxicity and Differentiating Effect of the Poly(ADP-Ribose) Polymerase Inhibitor Olaparib in Myelodysplastic Syndromes

Cancers, Vol. 11, Pages 1373: Cytotoxicity and Differentiating Effect of the Poly(ADP-Ribose) Polymerase Inhibitor Olaparib in Myelodysplastic Syndromes Cancers doi: 10.3390/cancers11091373 Authors: Isabella Faraoni Maria Irno Consalvo Francesca Aloisio Emiliano Fabiani Manuela Giansanti Francesca Di Cristino Giulia Falconi Lucio Tentori Ambra Di Veroli Paola Curzi Luca Maurillo Pasquale Niscola Francesco Lo-Coco Grazia Graziani Maria Teresa Voso 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 ar...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research