Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell-derived sarcomas. MPNSTs are the leading cause of mortality in patients with neurofibromatosis type 1 (NF1), an autosomal dominant genetic disease. Current treatment modalities have been ineffective resulting in high recurrence (40–68%) and poor five year survival rate between 16–52% in these tumors. This necessitates the need for novel therapeutic options. The anti-apoptotic members of the Bcl-2 family have been reported to be over expressed in a variety of cancers and have been implicated in rendering cancer cells resistant to apoptosis. Gossypol, a naturally occurring phenolic compound, functions as a BH3 mimetic by occupying the BH3-binding groove of anti-apoptotic proteins of the Bcl-2 family. Gossypol has been shown to induce cell death in prostate cancer, breast cancer, glioma and some hematological cancer cell lines. In this study, we assessed the effect of AT101 (gossypol) on MPNST cells. We observed that AT101 caused a dose and time dependent decrease in viability in MPNST cells which was not accompanied by an increase in caspase activation. AT101 also caused accumulation of autophagic vacuoles. Blocking the initiation of autophagy attenuated the cell death caused by AT101, while blocking apoptosis did not provide any protection. In summary, AT101 induces autophagic vacuole accumulation leading to cell death independent of caspase activation in MPNST cells. Further studies are needed to elucidate the mechanisms through which AT101 causes cell death in MPNSTs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A34.
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