Romidepsin (FK228) fails in counteracting the transformed phenotype of rhabdomyosarcoma cells but efficiently radiosensitizes, in vitro and in vivo, the alveolar phenotype subtype
| Autor: | Vincenzo Tombolini, Matteo Cassandri, Massimo Vergine, Irene Fasciani, Antonella Polimeni, Roberto Maggio, Luisa Milazzo, Alessandro Fanzani, Francesco Petragnano, Alessandra Rossetti, Cristina Antinozzi, Francesca De Felice, Luigi Di Luigi, Francesco Marampon, Giovanni Luca Gravina, Francesca Vulcano, Rossella Rota, Silvia Pomella, Francesca Cicchetti, Giampiero Macioce, Silvia Codenotti, Claudio Festuccia |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Radiation-Sensitizing Agents
FK228 FK228 Radioresistance Radiotherapy Rhabdomyosarcoma Romidepsin Cyclin A Apoptosis Cell Transformation Settore MED/05 030218 nuclear medicine & medical imaging Romidepsin Flow cytometry Cell Line 03 medical and health sciences Mice 0302 clinical medicine In vivo Radioresistance Cell Line Tumor Depsipeptides medicine Animals Humans romidepsin Radiology Nuclear Medicine and imaging Rhabdomyosarcoma PI3K/AKT/mTOR pathway radiotherapy Neoplastic Tumor Radiological and Ultrasound Technology biology medicine.diagnostic_test radioresistance Cell Differentiation Cell Transformation Neoplastic Phenotype Chemistry medicine.disease Cell culture 030220 oncology & carcinogenesis Cancer research biology.protein rhabdomyosarcoma medicine.drug |
| Popis: | PURPOSE Herein we describe the in vitro and in vivo activity of FK228 (Romidepsin), an inhibitor of class I HDACs, in counteracting and radiosensitizing embryonal (ERMS, fusion-negative) and alveolar (ARMS, fusion-positive) rhabdomyosarcoma (RMS). METHODS RH30 (ARMS, fusion-positive) and RD (ERMS, fusion-negative) cell lines and human multipotent mesenchymal stromal cells (HMSC) were used. Flow cytometry analysis, RT-qPCR, western blotting and enzymatic assays were performed. Irradiation was delivered by using an x-6 MV photon linear accelerator. FK228 (1.2 mg/kg) in vivo activity, combined or not with radiation therapy (2 Gy), was assessed in murine xenografts. RESULTS Compared to HMSC, RMS expressed low levels of class I HDACs. In vitro, FK228, as single agents, reversibly downregulated class I HDACs expression and activity and induced oxidative stress, DNA damage and a concomitant growth arrest associated with PARP-1-mediated transient non-apoptotic cell death. Surviving cells upregulated the expression of cyclin A, B, D1, p27, Myc and activated PI3K/Akt/mTOR and MAPK signaling, known to be differently involved in cancer chemoresistance. Interestingly, while no radiosensitizing effects were detected, in vitro or in vivo, on RD cells, FK228 markedly radiosensitized RH30 cells by impairing antioxidant and DSBs repair pathways in vitro. Further, FK228 when combined with RT in vivo significantly reduced tumor mass in mouse RH30 xenografts. CONCLUSION FK228 did not show antitumor activity as a single agent whilst its combination with RT resulted in radiosensitization of fusion-positive RMS cells, thus representing a possible strategy for the treatment of the most aggressive RMS subtype. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|