Abstract
BackgroundMany cancer cells develop resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, necessitating combination with chemotherapy, and normal cells manifest side effects due to the combined treatment regimen of TRAIL and chemotherapeutic drugs. A novel cancer therapy utilizing TRAIL is thus urgently needed.ResultsIn this study, we exploited TRAIL receptor-mediated endocytosis for the first time to produce a cell-permeable molecule, soluble forms of recombinant TRAIL:iron superoxide dismutase (sTRAIL:FeSOD), which possesses sTRAIL-induced apoptotic ability and FeSOD antioxidant activity. The FeSOD component was rapidly introduced into the cell by sTRAIL and intracellular superoxide radical (O2-), which have been implicated as potential modulators of apoptosis in cancer cells, was eliminated, resulting in a highly reduced cellular environment. The decrease in cellular O2-, which was accompanied by a brief accumulation of H2O2 and downregulation of phosphorylated Akt (p-Akt) and cellular FLICE-inhibitory protein, sensitized K562 leukemia cells and human promyelocytic leukemia (HL-60) cells to TRAIL-induced apoptosis. The low H2O2 levels protected human LO2 hepatocytes from sTRAIL:FeSOD-induced apoptosis despite downregulation of p-Akt. We also obtained evidence that the lack of response to sTRAIL:FeSOD in normal T cells occurred because sTRAIL:FeSOD shows much stronger shifts of redox state in erythroleukemia (K562) and HL-60 cells compared to that in normal T cells. K562 and HL-60 cells underwent sTRAIL:FeSOD-induced apoptosis without the dysfunction of mitochondria.ConclusionsThe fusion protein overcomes the inability of FeSOD to permeate the cell membrane, exhibits synergistic apoptotic effects on K562 and HL-60 cells and demonstrates minimal toxicity to normal T cells and the normal liver cell line LO2, indicating its potential value for the treatment of leukemia.
Highlights
Many cancer cells develop resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, necessitating combination with chemotherapy, and normal cells manifest side effects due to the combined treatment regimen of TRAIL and chemotherapeutic drugs
The internalization of FeSOD is indispensable for soluble forms of recombinant TRAIL (sTRAIL): FeSOD-induced apoptosis First, we examined the expression of TRAIL receptors and whether treatment with sTRAIL:FeSOD led to elevated surface expression of DR4 and DR5
To further assess the role of H2O2 produced during O2- scavenging in sTRAIL:FeSOD-induced apoptosis, we examined the apoptosis induced by sTRAIL:FeSOD after eliminating intracellular O2- by pretreating HL-60 and K562 cells with NAC for 24 hours (Figures 5I to 5K)
Summary
Many cancer cells develop resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, necessitating combination with chemotherapy, and normal cells manifest side effects due to the combined treatment regimen of TRAIL and chemotherapeutic drugs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anticancer therapeutic agent that induces apoptotic cell death in cancer cells [1], regardless of P53 status. Several different kinds of chemotherapy drugs are used in combination with TRAIL to sensitize TRAILresistant cancer cells, and many reports have combined recombinant TRAIL with standard anticancer therapies to induce synergistic tumor cell apoptosis [10,11]. Mutation or deletion of p53 occurs in more than half of all human tumors, and Akt is frequently hyperactive in cancer cells Both of these alterations play a prominent role in cell resistance to chemoradiotherapy. In recent years, biological mechanism-based cancer therapeutic strategies that may exert enhanced antitumor activity and high tumor specificity have attracted much more attention because of the unfavorable side effects of chemoradiotherapy and the resistance of many tumor cells to chemo- or radiotherapy [2,15]
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