Romidepsin (FK228) fails in counteracting the transformed phenotype of rhabdomyosarcoma cells but efficiently radiosensitizes, in vitro and in vivo, the alveolar phenotype subtype

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

“…Despite the triggering of DNA damage, the reduction of Reactive Oxygen species (ROS) associated with downregulation of antioxidant genes such as NRF2, SOD, CAT and GPx4 and the increase of G2 cell cycle arrest in both cell lines by the combination vs single treatments, co-treatment in RD cells did not show any enhancement of the inhibitor effect on colony formation, which was hindered only by RT. Interestingly, whereas in vivo RT treatment partially affected RD xenografts growth, it had no effects on RH30 xenografts suggesting they were resistant to RT, as already reported [37]. Conversely, MS-275 significantly inhibited RH30 tumor growth with modest effects on RD tumors.…”

“…Accordingly to the already collected evidence [3,4,27], MS-275 induced growth arrest that washout experiments showed to be irreversible in FP-RMS RH30. Of note, we have recently shown that also the only class I HDACi FK228 (Romidepsin) induced growth arrest, but this was reversible for both RD and RH30 cells since the washout of the drug reverted the cytotoxicity [37]. Furthermore, the strong response of RH30 cells to MS-275 is in line with the effects of the drug on cell cycle distribution, which underwent a drastic modification with a high percentage of cells rapidly arrested in the G1 phase and cells that continue to die after washout.…”

“…once daily for 5 consecutive days. Mice belonging to RT and MS-275+RT groups were irradiated with the dose of 2 Gy the 1st, 3rd and 5th day [37] one hour after receiving MS-275, for a total dose of 6 Gy. Tumor volumes were measured every 5 days for a period of 20 days after the starting of the treatment.…”

“…Class I and IV HDACs have been shown to be deregulated in RMS [3,4,6]. In in vitro and in vivo models of RMS several HDACi have been successfully preclinically tested, alone or in combination with chemotherapy (CHT) [26][27][28][29][30][31][32][33][34][35] or RT [36,37]. However, HDACi failed in treating RMS patients when used alone or in combination with CHT [38][39][40][41][42].…”

“…However, HDACi failed in treating RMS patients when used alone or in combination with CHT [38][39][40][41][42]. Recently, our group has elucidated the ability of two pan-HDACi to radiosensitize RMS cells in vitro and in vivo [36,37]. MS-275 (Entinostat), a potent class I and IV-selective HDACi [43], has been recently used in RMS xenograft models and in patients demonstrating modest antitumor activity alone and in combination with standard-of-care cytotoxic agents [33,34].…”