sepantronium and Nerve-Sheath-Neoplasms

To examine the role of survivin as a therapeutic target in preclinical models of human malignant peripheral nerve sheath tumors (MPNST) EXPERIMENTAL DESIGN: Survivin protein expression levels and subcellular localization were examined immunohistochemically in an MPNST tissue microarray. Human MPNST cells were studied in vitro and in vivo; real-time PCR, Western blotting, and immunocytochemical analyses were used to evaluate survivin expression and localization activation. Cell culture assays were used to evaluate the impact of anti-survivin-specific siRNA inhibition on cell growth and cell-cycle progression and survival. The effect of the small-molecule survivin inhibitor YM155 on local and metastatic MPNST growth was examined in vivo.. Survivin was found to be highly expressed in human MPNSTs; enhanced cytoplasmic subcellular localization differentiated MPNSTs from their plexiform neurofibroma premalignant counterparts. Human MPNST cell lines exhibited survivin mRNA and protein overexpression; expression in both nuclear and cytoplasmic compartments was noted. Survivin knockdown abrogated MPNST cell growth, inducing G(2) cell-cycle arrest and marked apoptosis. YM155 inhibited human MPNST xenograft growth and metastasis in severe combined immunodeficient (SCID) mice. Antitumor effects were more pronounced in fast-growing xenografts.. Our studies show an important role for survivin in human MPNST biology. Patients with MPNSTs should be considered for ongoing or future clinical trials that evaluate anti-survivin therapeutic strategies. Most importantly, future investigations should evaluate additional pathways that can be targeted in combination with survivin for maximal synergistic anti-MPNST effects.

Topics: Adult; Animals; Apoptosis; Blotting, Western; Cell Cycle; Cell Proliferation; Female; Fluorescent Antibody Technique; Humans; Imidazoles; Immunoenzyme Techniques; Inhibitor of Apoptosis Proteins; Mice; Mice, Hairless; Mice, SCID; Naphthoquinones; Nerve Sheath Neoplasms; Real-Time Polymerase Chain Reaction; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Schwann Cells; Survivin; Tissue Array Analysis; Xenograft Model Antitumor Assays