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.
Highlights
Glioblastoma (GBM) is the most common and lethal brain tumor and current standard therapies including surgery, chemotherapy and radiation provide no curative treatments
The results demonstrated that salinomycin enhanced TRAILinduced apoptosis, mainly by up-regulating the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-R2
We have evaluated the effect of salinomycin on the proliferation of three human glioblastoma cell lines, U87MG, U251 and T98G
Summary
Glioblastoma (GBM) is the most common and lethal brain tumor and current standard therapies including surgery, chemotherapy and radiation provide no curative treatments. A promising novel therapeutic approach for GBM is the reactivation of apoptosis by treatment with members of the tumor necrosis factor (TNF) family, of which the TNF-related apoptosis-inducing ligand (TRAIL) holds the greatest appeal [2]. TRAIL exerts its function by binding its membrane receptors, designated TRAIL-R1/DR4, TRAIL-R2/DR5, TRAIL-R3/ DcR1 and TRAIL-R4/DcR2. Of these receptors, only TRAILR1 and TRAIL-R2 transmit the apoptotic signal, while TRAILR3 and TRAIL-R4 are thought to function as decoy receptors that modulate TRAIL sensitivity [2]. A considerable number of cancer cell types, including glioblastoma, have been found to be resistant to the apoptotic stimuli of TRAIL. The combination of TRAIL with small molecules has been investigated as a strategy to potentiate TRAIL cytotoxicity by the sensitization of TRAILresistant cancer cells [5]
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