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 mu M (2.0-24.8 mu M), lower than plasma peak concentration reached in vivo. In addition, olaparib induced DNA damage as shown by a high proportion of gamma H2AX positive cells in samples with low IC(50)s. 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.

Faraoni, I., Consalvo, M.i., Aloisio, F., Fabiani, E., Giansanti, M., Di Cristino, F., et al. (2019). Cytotoxicity and differentiating effect of the poly(ADP-ribose) polymerase inhibitor olaparib in myelodysplastic syndromes. CANCERS, 11(9), 1373 [10.3390/cancers11091373].

Cytotoxicity and differentiating effect of the poly(ADP-ribose) polymerase inhibitor olaparib in myelodysplastic syndromes

Faraoni I.;Tentori L.;Di Veroli A.;Lo-Coco F.;Graziani G.;Voso M. T.
2019-01-01

Abstract

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 mu M (2.0-24.8 mu M), lower than plasma peak concentration reached in vivo. In addition, olaparib induced DNA damage as shown by a high proportion of gamma H2AX positive cells in samples with low IC(50)s. 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.
2019
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14 - FARMACOLOGIA
English
AML; MDS; PARP inhibitors; PARP1; hematopoietic differentiation; olaparib
Faraoni, I., Consalvo, M.i., Aloisio, F., Fabiani, E., Giansanti, M., Di Cristino, F., et al. (2019). Cytotoxicity and differentiating effect of the poly(ADP-ribose) polymerase inhibitor olaparib in myelodysplastic syndromes. CANCERS, 11(9), 1373 [10.3390/cancers11091373].
Faraoni, I; Consalvo, Mi; Aloisio, F; Fabiani, E; Giansanti, M; Di Cristino, F; Falconi, G; Tentori, L; Di Veroli, A; Curzi, P; Maurillo, L; Niscola, P; Lo-Coco, F; Graziani, G; Voso, Mt
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/226882
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