Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor-related apoptosisinducing ligand and induces an alternative cell death pathway

Neuroscience Center and Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Neuro-Oncology (Impact Factor: 5.56). 07/2011; 13(11):1213-24. DOI: 10.1093/neuonc/nor067
Source: PubMed


Human glioblastoma (GBM) cells are notorious for their resistance to apoptosis-inducing therapeutics. We have identified lanatoside C as a sensitizer of GBM cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death partly by upregulation of the death receptor 5. We show that lanatoside C sensitizes GBM cells to TRAIL-induced apoptosis in a GBM xenograft model in vivo. Lanatoside C on its own serves as a therapeutic agent against GBM by activating a caspase-independent cell death pathway. Cells treated with lanatoside C showed necrotic cell morphology with absence of caspase activation, low mitochondrial membrane potential, and early intracellular ATP depletion. In conclusion, lanatoside C sensitizes GBM cells to TRAIL-induced cell death and mitigates apoptosis resistance of glioblastoma cells by inducing an alternative cell death pathway. To our knowledge, this is one of the first examples of use of caspase-independent cell death inducers to trigger tumor regression in vivo. Activation of such mechanism may be a useful strategy to counter resistance of cancer cells to apoptosis.

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Available from: Christian E Badr, May 15, 2014
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    • "Lanatoside C. Badr et al. [48] identified the cardenolide lanatoside C as a sensitizer of glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. They observed that lanatoside C, alone or in combination with TRAIL, reduced tumor growth in nude mice harboring human U87 glioblastoma cells. "
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    BioMed Research International 05/2014; 2014(12):794930. DOI:10.1155/2014/794930 · 3.17 Impact Factor
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    • "First, TRAIL-R2, but not TRAIL-R1, is the main TRAIL receptor expressed on glioblastoma cells and its activation may trigger caspase-8 cleavage and initiation of apoptosis [29]. Second, several agents that upmodulate TRAIL-R2 expression in glioblastoma cells, such as cisplatin [30], lanatoside C [31], nelfinavir [32], the protesome inhibitor SC68896 [33] restore TRAIL sensitivity of glioblastoma cells. Third, the level of TRAIL-R2 expression on glioblastoma cells positively correlates with patient's survival and alone represents an independent and significant prognostic factor for survival [34]. "
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    ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to exhibit therapeutic activity in cancer. However, many tumors remain resistant to treatment with TRAIL. Therefore, small molecules that potentiate the cytotoxic effects of TRAIL could be used for combinatorial therapy. Here we found that the ionophore antibiotic salinomycin acts in synergism with TRAIL, enhancing TRAIL-induced apoptosis in glioma cells. Treatment with low doses of salinomycin in combination with TRAIL augmented the activation of caspase-3 and increased TRAIL-R2 cell surface expression. TRAIL-R2 upmodulation was required for mediating the stimulatory effect of salinomycin on TRAIL-mediated apoptosis, since it was abrogated by siRNA-mediated TRAIL-R2 knockdown. Salinomycin in synergism with TRAIL exerts a marked anti-tumor effect in nude mice xenografted with human glioblastoma cells. Our results suggest that the combination of TRAIL and salinomycin may be a useful tool to overcome TRAIL resistance in glioma cells and may represent a potential drug for treatment of these tumors. Importantly, salinomycin+TRAIL were able to induce cell death of well-defined glioblastoma stem-like lines.
    PLoS ONE 04/2014; 9(4):e94438. DOI:10.1371/journal.pone.0094438 · 3.23 Impact Factor
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    • "Cluster C contains a number of structurally related cardenolide glycosides (digoxin; lanatoside C; peruvoside; neriifolin; digitoxin), characterized by reduced cell size, condensed nuclei, plasma membrane blebbing, reduced nucleolar staining, and significant cytotoxicity (Text S2). While compounds of this class are thought to affect a range of biological processes, their effects on morphology are consistent with their reported ability to cause cell death [18,19]. "
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