MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells

• Published in: International journal of molecular sciences 2021-10, Vol.22 (19), p.10671
• Main Authors: Cassandri, Matteo, Pomella, Silvia, Rossetti, Alessandra, Petragnano, Francesco, Milazzo, Luisa, Vulcano, Francesca, Camero, Simona, Codenotti, Silvia, Cicchetti, Francesca, Maggio, Roberto, Festuccia, Claudio, Gravina, Giovanni Luca, Fanzani, Alessandro, Megiorni, Francesca, Catanoso, Marialuigia, Marchese, Cinzia, Tombolini, Vincenzo, Locatelli, Franco, Rota, Rossella, Marampon, Francesco
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Antioxidants; Apoptosis; c-Myc protein; Cell cycle; Chemotherapy; Children; Cyclin A; Cyclin-dependent kinases; Cytotoxicity; DNA damage; DNA repair; Epigenetics; FOXO1 protein; Gene expression; HDACs; Histone deacetylase; Kinases; Medical prognosis; Metastases; MS-275; Mutation; Myc protein; Oxidants; Oxidizing agents; Pax3 protein; pediatric cancers; Phosphorylation; Radiation therapy; radiotherapy; Reactive oxygen species; Rhabdomyosarcoma; Soft tissue sarcoma; Soft tissues; TOR protein; Tumors; Xenografts; Xenotransplantation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms221910671

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS.