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

被引：19

作者：

Cassandri, Matteo ^{[1
,2
]}

Pomella, Silvia ^{[2
]}

Rossetti, Alessandra ^{[3
]}

Petragnano, Francesco ^{[3
]}

Milazzo, Luisa ^{[4
]}

Vulcano, Francesca ^{[4
]}

Camero, Simona ^{[5
]}

Codenotti, Silvia ^{[6
]}

Cicchetti, Francesca ^{[7
]}

Maggio, Roberto ^{[3
]}

Festuccia, Claudio ^{[3
]}

Gravina, Giovanni Luca ^{[3
]}

Fanzani, Alessandro ^{[6
]}

Megiorni, Francesca ^{[8
]}

Catanoso, Marialuigia ^{[2
]}

Marchese, Cinzia ^{[8
]}

Tombolini, Vincenzo ^{[1
]}

Locatelli, Franco ^{[2
,9
]}

Rota, Rossella ^{[2
]}

Marampon, Francesco ^{[1
]}

机构：

[1] Sapienza Univ Rome, Policlin Umberto I, Dept Radiotherapy, I-00161 Rome, Italy

[2] IRCCS, Bambino Gesu Childrens Hosp, Dept Oncohematol, I-00146 Rome, Italy

[3] Univ Aquila, Dept Biotechnol & Appl Clin Sci, I-67100 LAquila, Italy

[4] Ist Super Sanita, Dept Oncol & Mol Med, I-00161 Rome, Italy

[5] Sapienza Univ Rome, Dept Maternal & Child & Urol Sci, I-00161 Rome, Italy

[6] Univ Brescia, Div Biotechnol, Dept Mol & Translat Med, I-25121 Brescia, Italy

[7] Policlin Umberto I Hosp, Viale Policlin, I-00161 Rome, Italy

[8] Sapienza Univ Rome, Dept Expt Med, Viale Regina Elena 324, I-00161 Rome, Italy

[9] Sapienza Univ Rome, Dept Gynecol Obstet & Pediat, I-00161 Rome, Italy

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2021年 / 22卷 / 19期

关键词：

rhabdomyosarcoma; radiotherapy; MS-275; HDACs; pediatric cancers; soft tissue sarcoma; DNA damage; HISTONE DEACETYLASE INHIBITOR; VIVO ANTITUMOR-ACTIVITY; EMBRYONAL RHABDOMYOSARCOMA; ACCELERATED REPOPULATION; DNA-DAMAGE; PHASE-II; CANCER; RESISTANCE; RADIOTHERAPY; RADIORESISTANCE;

D O I：

10.3390/ijms221910671

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：23