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MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells
Matteo Cassandri1,2, Silvia Pomella2, Alessandra Rossetti3
1Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy.
Abstract:
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.
Insights
MS-275 (Entinostat), a HDAC inhibitor, enhances radiotherapy effectiveness in fusion-positive rhabdomyosarcoma (RMS) by increasing DNA damage and reducing antioxidant defenses. This combination therapy shows promise for treating radio-resistant pediatric soft tissue sarcoma.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma.
- Fusion-positive (FP)-RMS, driven by PAX3/PAX7-FOXO1 oncoproteins, and fusion-negative (FN)-RMS with RAS mutations represent distinct subtypes.
- Metastatic RMS often exhibits radio-resistance, limiting radiotherapy's efficacy.
Purpose of the Study:
- To investigate the efficacy of MS-275 (Entinostat), a histone deacetylase inhibitor (HDACi), in combination with radiotherapy (RT) for rhabdomyosarcoma.
- To evaluate the molecular mechanisms underlying the radio-sensitizing effects of MS-275 in both FP-RMS and FN-RMS cell lines.
- To assess the in vitro and in vivo therapeutic potential of MS-275 and RT combination therapy.
Main Methods:
- In vitro studies using FN-RMS (RD) and FP-RMS (RH30) cell lines treated with MS-275 and/or RT.
- Analysis of cell survival, cell cycle progression, gene expression (cyclins, p21, p27, NRF2, antioxidant genes), protein activity (ERK, PI3K/Akt/mTOR), and DNA damage markers.
- In vivo studies involving RH30 xenografts to evaluate tumor growth inhibition.
Main Results:
- MS-275 differentially affected cell survival in RD and RH30 cell lines, altering key cell cycle regulators and signaling pathways.
- The combination of MS-275 and RT reduced colony formation, increased DNA damage, inhibited repair, elevated reactive oxygen species, and downregulated antioxidant genes (NRF2, SOD, CAT, GPx4).
- MS-275 potentiated RT-induced G2 growth arrest and demonstrated significant in vivo tumor growth inhibition, completely preventing the growth of radio-resistant RH30 xenografts when combined with radiation.
Conclusions:
- MS-275 exhibits potent radio-sensitizing effects in rhabdomyosarcoma cells, particularly in the fusion-positive subtype.
- The combination therapy enhances DNA damage and oxidative stress while suppressing antioxidant defenses, leading to improved therapeutic outcomes.
- MS-275 represents a promising therapeutic agent for overcoming intrinsic radio-resistance in PAX3-FOXO1 driven RMS.
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