TY - JOUR
T1 - The botanical drug PBI-05204, a supercritical CO2 extract of Nerium oleander, sensitizes alveolar and embryonal rhabdomyosarcoma to radiotherapy in vitro and in vivo
AU - Vaccaro, Sara
AU - Rossetti, Alessandra
AU - Porrazzo, Antonella
AU - Camero, Simona
AU - Cassandri, Matteo
AU - Pomella, Silvia
AU - Tomaciello, Miriam
AU - Macioce, Giampiero
AU - Pedini, Francesca
AU - Barillari, Giovanni
AU - Marchese, Cinzia
AU - Rota, Rossella
AU - Cenci, Giovanni
AU - Tombolini, Mario
AU - Newman, Robert A.
AU - Yang, Peiying
AU - Codenotti, Silvia
AU - Fanzani, Alessandro
AU - Megiorni, Francesca
AU - Festuccia, Claudio
AU - Minniti, Giuseppe
AU - Gravina, Giovanni Luca
AU - Vulcano, Francesca
AU - Milazzo, Luisa
AU - Marampon, Francesco
N1 - Publisher Copyright:
Copyright © 2022 Vaccaro, Rossetti, Porrazzo, Camero, Cassandri, Pomella, Tomaciello, Macioce, Pedini, Barillari, Marchese, Rota, Cenci, Tombolini, Newman, Yang, Codenotti, Fanzani, Megiorni, Festuccia, Minniti, Gravina, Vulcano, Milazzo and Marampon.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Treatment of rhabdomyosarcoma (RMS), the most common a soft tissue sarcoma in childhood, provides intensive multimodal therapy, with radiotherapy (RT) playing a critical role for local tumor control. However, since RMS efficiently activates mechanisms of resistance to therapies, despite improvements, the prognosis remains still largely unsatisfactory, mainly in RMS expressing chimeric oncoproteins PAX3/PAX7-FOXO1, and fusion-positive (FP)-RMS. Cardiac glycosides (CGs), plant-derived steroid-like compounds with a selective inhibitory activity of the Na+/K+-ATPase pump (NKA), have shown antitumor and radio-sensitizing properties. Herein, the therapeutic properties of PBI-05204, an extract from Nerium oleander containing the CG oleandrin already studied in phase I and II clinical trials for cancer patients, were investigated, in vitro and in vivo, against FN- and FP-RMS cancer models. PBI-05204 induced growth arrest in a concentration dependent manner, with FP-RMS being more sensitive than FN-RMS, by differently regulating cell cycle regulators and commonly upregulating cell cycle inhibitors p21Waf1/Cip1 and p27Cip1/Kip1. Furthermore, PBI-05204 concomitantly induced cell death on both RMS types and senescence in FN-RMS. Notably, PBI-05204 counteracted in vitro migration and invasion abilities and suppressed the formation of spheroids enriched in CD133+ cancer stem cells (CSCs). PBI-05204 sensitized both cell types to RT by improving the ability of RT to induce G2 growth arrest and counteracting the RT-induced activation of both Non‐Homologous End‐Joining and homologous recombination DSBs repair pathways. Finally, the antitumor and radio-sensitizing proprieties of PBI-05204 were confirmed in vivo. Notably, both in vitro and in vivo evidence confirmed the higher sensitivity to PBI-05204 of FP-RMS. Thus, PBI-05204 represents a valid radio-sensitizing agent for the treatment of RMS, including the intrinsically radio-resistant FP-RMS.
AB - Treatment of rhabdomyosarcoma (RMS), the most common a soft tissue sarcoma in childhood, provides intensive multimodal therapy, with radiotherapy (RT) playing a critical role for local tumor control. However, since RMS efficiently activates mechanisms of resistance to therapies, despite improvements, the prognosis remains still largely unsatisfactory, mainly in RMS expressing chimeric oncoproteins PAX3/PAX7-FOXO1, and fusion-positive (FP)-RMS. Cardiac glycosides (CGs), plant-derived steroid-like compounds with a selective inhibitory activity of the Na+/K+-ATPase pump (NKA), have shown antitumor and radio-sensitizing properties. Herein, the therapeutic properties of PBI-05204, an extract from Nerium oleander containing the CG oleandrin already studied in phase I and II clinical trials for cancer patients, were investigated, in vitro and in vivo, against FN- and FP-RMS cancer models. PBI-05204 induced growth arrest in a concentration dependent manner, with FP-RMS being more sensitive than FN-RMS, by differently regulating cell cycle regulators and commonly upregulating cell cycle inhibitors p21Waf1/Cip1 and p27Cip1/Kip1. Furthermore, PBI-05204 concomitantly induced cell death on both RMS types and senescence in FN-RMS. Notably, PBI-05204 counteracted in vitro migration and invasion abilities and suppressed the formation of spheroids enriched in CD133+ cancer stem cells (CSCs). PBI-05204 sensitized both cell types to RT by improving the ability of RT to induce G2 growth arrest and counteracting the RT-induced activation of both Non‐Homologous End‐Joining and homologous recombination DSBs repair pathways. Finally, the antitumor and radio-sensitizing proprieties of PBI-05204 were confirmed in vivo. Notably, both in vitro and in vivo evidence confirmed the higher sensitivity to PBI-05204 of FP-RMS. Thus, PBI-05204 represents a valid radio-sensitizing agent for the treatment of RMS, including the intrinsically radio-resistant FP-RMS.
KW - Na/K +ATPase
KW - oleandrin
KW - PBI-05204
KW - radiosenisitizing agent
KW - radiotherapy
KW - rhabdomyosarcoma
UR - http://www.scopus.com/inward/record.url?scp=85144025452&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85144025452&partnerID=8YFLogxK
U2 - 10.3389/fphar.2022.1071176
DO - 10.3389/fphar.2022.1071176
M3 - Article
C2 - 36532747
AN - SCOPUS:85144025452
SN - 1663-9812
VL - 13
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 1071176
ER -