title: Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice.
abstract: Rhadbomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and is subdivided in the embryonal (ERMS) and alveolar (ARMS) subtypes, the latter being associated with the worst prognosis. We report that sulforaphane (SFN), a broccoli-derived anticancer isothiocyanate, causes dose- and time-dependent growth inhibition and apoptosis in both ERMS and ARMS cells. In ARMS, SFN induced the modulation of expression of crucial genes and proteins: mRNA and protein levels of PAX3-FKHR, MYCN, and MET decreased, while those of p21 and TRAIL-receptor DR5 (but not DR4) increased. Since DR5 expression increased specifically in ARMS, we treated ARMS cells with TRAIL, SFN, or their combination. While ARMS cells (RH30 and RH4) proved to be TRAIL-resistant, SFN restored their sensitivity to TRAIL-induced cell-growth inhibition, leading to a stronger effect in combination with TRAIL. ARMS cells transfected with siDR5 showed that SFN-induced DR5 acts as a key regulator, being directly related to the TRAIL-induced cell-growth inhibition. The in vivo anti-tumor activity of SFN and TRAIL was evaluated in a xenograft murine model of ARMS through microPET. The results showed that the systemic treatment (3 wk) of mice with SFN or TRAIL as single agents only delayed tumor evolution, while the combined treatment of SFN and TRAIL led to tumor elimination. These findings indicate that SFN triggers the apoptotic pathway in both alveolar and embryonal rhabdomyosarcomas and that combined treatment with SFN and TRAIL might be a promising therapy for the aggressive alveolar subtype.
authors: Department of Pharmacy and Biotechnology; University of Bologna; Bologna, Italy.
authors: Elisa
authors: E
authors: Bergantin
authors: Department of Specialized, Diagnostic and Experimental Medicine; University of Bologna; Bologna, Italy.
authors: Carmelo
authors: C
authors: Quarta
authors: Department of Specialized, Diagnostic and Experimental Medicine; University of Bologna; Bologna, Italy.
authors: Cristina
authors: C
authors: Nanni
authors: Department of Specialized, Diagnostic and Experimental Medicine; University of Bologna; Bologna, Italy.
authors: Stefano
authors: S
authors: Fanti
authors: Department of Medical and Surgical Sciences; University of Bologna; Bologna, Italy.
authors: Andrea
authors: A
authors: Pession
authors: Department of Sciences for the Quality of Life; University of Bologna; Rimini, Italy.
authors: Giorgio
authors: G
authors: Cantelli-Forti
authors: Department of Pharmacy and Biotechnology; University of Bologna; Bologna, Italy.
authors: Roberto
authors: R
authors: Tonelli
authors: Department of Pharmacy and Biotechnology; University of Bologna; Bologna, Italy.
authors: Patrizia
authors: P
authors: Hrelia
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D064593:Heterografts; D006801:Humans; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology*; D008819:Mice, Nude; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D018232:Rhabdomyosarcoma, Alveolar / Q000188:drug therapy* / Q000473:pathology; D018233:Rhabdomyosarcoma, Embryonal / Q000188:drug therapy* / Q000473:pathology; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D017879:Isothiocyanates; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand; C016766:sulforaphane
keywords: TRAIL; alveolar; combination therapy; rhabdomyosarcoma; sulforaphane