Targeted inhibition of histone deacetylases and hedgehog signaling suppress tumor growth and homologous recombination in aerodigestive cancers.

摘要: Standard combined modality therapies for aerodigestive tract malignancies have suboptimal outcomes, and targeting cancer-specific molecular pathways in combination with radiation could improve the therapeutic ratio. Dysregulation of epigenetic modulators such as histone deacetylases (HDACs), developmental morphogens hedgehog (HH) pathway been implicated tumor progression metastasis. We hypothesized that simultaneous HDACs HH-pathway mediator Smoothened (Smo) represents an opportunity to overcome resistance these cancers. evaluated effects HDAC inhibitor SAHA Smo GDC-0449 multiple cancer cell lines. Isobologram analyses showed synergistically suppressed proliferation vitro. cooperatively enhanced G0/G1 cycle arrest which was associated up-regulation p21waf. prevented SAHA-induced Gli-1 Gli-2. Both Ptc-1 expression by GDC-0449. The induced sensitization 2 Gy determined colony formation assays cytogenetic analyses, correlated higher residual γ-H2AX 53BP1 foci. In mouse xenografts SqCC/Y1 line, delayed growth longer prolonged survival more than either agent alone. summary, we identified synergistic effect HH signaling radiosensitization outcomes malignancies.