lanatoside-c and Glioblastoma

The tumor-tropic properties of neural stem cells (NSCs) have been shown to serve as a novel strategy to deliver therapeutic genes to tumors. Recently, we have reported that the cardiac glycoside lanatoside C (Lan C) sensitizes glioma cells to the anticancer agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we engineered an FDA-approved human NSC line to synthesize and secrete TRAIL and the Gaussia luciferase (Gluc) blood reporter. We showed that upon systemic injection, these cells selectively migrate toward tumors in the mice brain across the blood-brain barrier, target invasive glioma stem-like cells, and induce tumor regression when combined with Lan C. Gluc blood assay revealed that 30% of NSCs survived 1 day postsystemic injection and around 0.5% of these cells remained viable after 5 weeks in glioma-bearing mice. This study demonstrates the potential of systemic injection of NSCs to deliver anticancer agents, such as TRAIL, which yields glioma regression when combined with Lan C.

Topics: Animals; Apoptosis; Brain Neoplasms; Cardiac Glycosides; Cell Line, Tumor; Cell Movement; Coculture Techniques; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Genetic Therapy; Glioblastoma; Humans; Lanatosides; Mice; Mice, Nude; Neural Stem Cells; TNF-Related Apoptosis-Inducing Ligand; Transfection; Xenograft Model Antitumor Assays

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.

Topics: Animals; Apoptosis; Autophagy; Blotting, Western; Brain Neoplasms; Caspases; Cell Death; Cells, Cultured; Drug Resistance, Neoplasm; Glioblastoma; Humans; Lanatosides; Mice; Mice, Nude; Necrosis; Real-Time Polymerase Chain Reaction; Receptors, TNF-Related Apoptosis-Inducing Ligand; RNA, Messenger; TNF-Related Apoptosis-Inducing Ligand