CHARACTERIZATION OF ADRB2-MEDIATED ANTITUMORAL EFFECTS AND MECHANISMS OF ACTION OF β-BLOCKER PROPRANOLOL IN OSTEOSARCOMA

SOLERNÓ LM; SOBOL NT; FERRERO MR; LLAVONA C; CAPOBIANCO CS; BRUZZONE A; GOTTARDO MF; GARONA J

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

Sociedad Argentina de Investigación Clínica

Osteosarcoma (OSA) is still associated with limited response tostandard-of-care therapy and alarmingly elevated mortality rates.Our group recently reported for the first time that PPN, a repurposedβ1/2-adrenergic receptor (ADRB1/2) antagonist, was capable ofreducing tumor-associated angiogenesis and xenograft aggres-siveness using different OSA preclinical models. The objective ofthis work was to characterize PPN ADRB2-mediated effects andmechanisms of action on OSA growth, migration and response tochemotherapy. After confirming ADRB2 expression by RT-qPCRin MG-63 and U-2OS OSA cells, pro-mitogenic effects of ADRBagonists epinephrine and norepinephrine were associated withdownstream activation of MAPK-associated signaling pathways,as evaluated by western blotting. ADRB2 knockdown by transfec-tion with ADRB2-targeting siRNA reduced in vitro aggressivenessof OSA cells and impaired PPN cytostatic activity, confirming targetspecificity of the drug. As evaluated by flow cytometry, a significantarrest in the G0/G1cell cycle phase of MG-63 and U-2OS cells wasobserved after 24 h treatment with PPN (50 μM), which was as-sociated with a significant reduction in CCND1 gene expression, akey cell cycle regulator. OSA growth inhibition was not associatedwith apoptosis induction. β-blockade with PPN inhibited OSA cellchemotaxis, vasculogenic mimicry and capillary-like tube formationon Matrigel® coated substrates. Migration inhibition was linked toblockade of EGF-induced actin reorganization and stress fiber for-mation. After histological analysis, in vivo therapeutic benefits af-ter addition of PPN (10 mg/kg i.p.) to cisplatin-based metronomicchemotherapy (2 mg/kg i.p.) correlated with reduced tumor mitoticindex and increased necrosis. All results were significant at p