Purpose of the Study Despite significant advances in diagnosis and treatment of head and neck cancer, there has been little evidence of improvement in survival rates. Therefore, the development of new anticancer agents with different modes of action is of key importance in overcoming cancer resistance to therapy. Recently, acid ceramidase protein has been identified as a potential target in regulation of cell survival and cancer response to treatment where its modulation played an important role in the efficacy of known apoptosis-inducing agents. In this study, we test the hypothesis that combination of the lysomotropic acid ceramidase inhibitor LCL 204 with FasL gene therapy can enhance its therapeutic efficiency for head and neck cancer.
Methods Protein analysis of tumor tissues was done using Western blotting, and cytotoxicity was measured using MTS viability assay.
Summary of Results First, we show using that acid ceramidase is significantly overexpressed in about 70% of head and neck cancer tumor tissues compared with normal tissues and that its overexpression mediates resistance to FasL gene therapy. Next, we show that acid ceramidase targeting using specific acid ceramidase siRNA can sensitize the head and neck cell line SCC-1 to FasL-induced apoptosis. In addition, we introduce the novel acid ceramidase inhibitor LCL204, capable of inducing more than 90% cell death in cells that overexpress acid ceramidase. At subtoxic doses, LCL204 also enhanced FasL cell killing by as much as 30%. Finally, using SCC-14A nude mice xenographs, we show that combination of FasL-gene therapy with LCL 204 was able to significantly enhance tumors response and mice survival compared with each treatment alone, with complete tumor regression in 100% of the mice receiving combination treatment.
Conclusion Taken together, these results indicate that combination gene therapy is worth investigation as a new alternative therapy for the treatment of head and neck cancer.
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