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  • Curcumin downregulates pro-survival proteins and induces cell death in GBM stem cells

    Final Number:
    493

    Authors:
    Zachary C Gersey BS; Ashish Harish Shah MD; Amade Bregy MD PhD; Bayou Zhang MD; Kelichi Ohaeto; Ahmed Alshareef MD; Kyriakos Papadmitriou MD; Winston Walters; Ricardo Jorge Komotar MD; Regina Graham

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2014 Annual Meeting

    Introduction: Glioblastoma Multiforme (GBM) is the most common and lethal form of brain tumor in adults. Following standard treatment of surgery, radiation, and chemotherapy, patients are expected to survive 12-14 months. Theorized cause of disease recurrence in these patients is tumor cell repopulation through the proliferation of treatment-resistant cancer stem cells. Current research has revealed Curcumin, principal ingredient in turmeric, can modulate multiple signalling pathways important for cancer stem cell self-renewal and survival. Here we evaluate the effects of curcumin on six patient-derived GBM stem cell lines.

    Methods: With patient consent and following surgical resection, GBM tumors were dissociated and single cells were plated in neurosphere media to enrich for tumor stem cells. Cells were characterized by immunocytochemistry. Effect of curcumin and temozolomide (current GBM chemotherapy) on cell viability was determined by MTS assay. Effects of curcumin on signalling pathways were elucidated by western blotting and curcumin induced caspase activity was determined with CellEvent caspase 3/7 reagent.

    Results: GBM stem cells were positive for stem cell markers nestin, CD133, musashi, and bmi1. Curcumin inhibited neurosphere formation and induced a dose-dependent decrease in cell viability. The IC50 of curcumin ranged between 15.6 µM- 29.3 µM for all but one cell line, which had an IC50 of 46.5 µM. In contrast, temozolomide (100 µM) had no effect on GBM stem cell viability. Furthermore, curcumin significantly decreased pro-survival proteins Bcl-2 and survivin and activated caspases, indicating apoptotic cell death.

    Conclusions: Bcl-2 and Survivin are overexpressed in drug resistant cancers. In fact, increased survivin in GBM correlates with poor prognosis. Our data suggests that curcumin induces GBM apoptotic stem cell death in part by down regulation of these anti-apoptotic proteins. By eliminating GBM stem cells, curcumin may prevent tumor recurrence and improve patient outcome.

    Patient Care: Curcumin is an effective GBM treatment in vitro and displays potent abilities to inhibit cell proliferation, migration, and invasion, induce apoptosis, induce differentiation in glial initiating cells, and cross the BBB, with insignificant toxic effects to healthy astrocytes. In addition, curcumin remains a natural compound that has already been successfully utilized in a variety of clinical trials including colorectal cancer and Alzheimer's. Therefore, we plan on further investigating its role in mice GBM xenotransplant models. Ultimately, the goal of this study suggests that curcumin may be a suitable therapeutic option for glioblastoma patients.

    Learning Objectives: - Glioblastoma stem-cell lines are highly resistant to traditional chemotherapeutics, and may be responsible for disease progression -Curcumin, a natural compound, decreases viability of these chemoresistant stem-cell lines by acting on bcl-2 and survivin pathways.

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