Poly(ADP-ribose) polymerase inhibitor olaparib hampers placental growth factor-driven activation of myelomonocytic cells.
Oncol Rep
; 39(5): 2261-2269, 2018 May.
Article
en En
| MEDLINE
| ID: mdl-29512738
ABSTRACT
The vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor activated by the angiogenic factors VEGFA and placental growth factor (PlGF). While VEGFA binds to both VEGFR1 and VEGFR2, PlGF interacts exclusively with VEGFR1 triggering a signaling pathway involved in i) tumorassociated angiogenesis; ii) chemotaxis and invasion of the extracellular matrix (ECM) by cancer cells; and iii) mobilization of bone marrowderived myeloid cells that generate tumorassociated macrophages. By using a novel antiVEGFR1 monoclonal antibody (D16F7 mAb), which hampers receptor activation without avoiding ligand binding, we recently demonstrated that VEGFR1 blockade reduced myeloid progenitor mobilization and monocyte/macrophage cell infiltration of tumor grafts in vivo. Since poly(ADPribose) polymerase (PARP)1 exerts a proinflammatory role favoring monocyte activation, in the present study we investigated whether the PARP inhibitor (PARPi) olaparib hampers PlGFinduced activation of human myelomonocytic cells. HL60 cells induced to differentiate towards the monocytic/macrophage lineage were tested and the results were confirmed in freshly isolated monocytes obtained from healthy donors. Cells were treated with olaparib, at clinically achievable concentrations, before exposure to PlGF and were analyzed for migration and ECM invasion in response to PlGF. Olaparib effects were compared to those obtained with D16F7 mAb used as single agent or in combination with the PARPi. The results indicate that differentiated HL60 cells and monocytes expressed VEGFR1 and migrated in response to PlGF. Moreover, olaparib and D16F7 inhibited PlGFinduced chemotaxis and ECM invasion in a dosedependent manner and with similar efficacy. However, in combination studies the PARPi and D16F7 did not exert synergistic effects. Olaparib also hampered PlGFinduced monocyte adhesion to fibronectin, while it did not affect NFκB activation in response to the angiogenic factor. These data suggest that olaparib likely interferes with the same pathway affected by the antiVEGFR1 mAb and that inhibition of PlGF-induced monocyte activation may contribute to PARPi antitumor activity.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ftalazinas
/
Piperazinas
/
Monocitos
/
Células Mieloides
/
Inhibidores de Poli(ADP-Ribosa) Polimerasas
/
Factor de Crecimiento Placentario
Límite:
Humans
Idioma:
En
Revista:
Oncol Rep
Asunto de la revista:
NEOPLASIAS
Año:
2018
Tipo del documento:
Article
País de afiliación:
Italia