Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice
Cancer Biology & Therapy. 2014-06-27; 15(9): 1219-1225
DOI: 10.4161/cbt.29684
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Bergantin E(1), Quarta C(2), Nanni C(2), Fanti S(2), Pession A(3), Cantelli-Forti
G(4), Tonelli R(1), Hrelia P(1).
Author information:
(1)Department of Pharmacy and Biotechnology; University of Bologna; Bologna,
Italy.
(2)Department of Specialized, Diagnostic and Experimental Medicine; University of
Bologna; Bologna, Italy.
(3)Department of Medical and Surgical Sciences; University of Bologna; Bologna,
Italy.
(4)Department of Sciences for the Quality of Life; University of Bologna; Rimini,
Italy.
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.