The use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic effect on cancer by overcoming a high apoptotic threshold. Here, we showed that phytosphingosine treatment in combination with ␥-radiation enhanced apoptotic cell death of radiation-resistant human T-cell lymphoma in a caspase-independent manner. Combination treatment induced an increase in intracellular reactive oxygen species ( results demonstrate that enhancement of cell death of radiation-resistant cancer cells by phytosphingosine treatment in combination with ␥-radiation is mediated by nuclear translocation of AIF, which is in turn mediated both by ROS-dependent Bax relocalization and ROS-independent PARP-1 activation. The molecular signaling pathways that we elucidated in this study may provide potential drug targets for radiation sensitization of cancers refractive to radiation therapy.
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