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TNFα was initially described as inducing necrotic death in tumors in vivo, and more recently as a cytokine that mediates cytoprotection and inflammation. The anti-tumor effects of TNFα are poorly characterized because TNFα- induced death of human tumor cells has largely been studied in the presence of agents that block transcription or protein synthesis. Also, most reports in model cell systems describe apoptosis within relatively early time points as the principal mode of cell death induced by TNFα. We investigated the cytotoxic effects of 10 ng/ml TNFα on human tumor cells of different histological types without concomitant exposure to these inhibitors. Eleven of 21 human tumor cell lines underwent TNFα-induced cell death which ranged from 41% to complete loss of viability. Only one cell line demonstrated caspase-dependent apoptosis within 24 h. Nine cell lines underwent death between 48 h and 21 days. Seven of these lines underwent caspase-3 independent death consistent with necrosis. One tumor line exhibited characteristics of senescence following TNFα exposure. Nine of 9 cell lines activated NF-κB following TNFα exposure by 24 h. In all cell lines studied, with the exception of the epidermoid carcinoma cell line that underwent early apoptosis, expression of one or more NF-κB target genes was demonstrated at 24-96 h. BMS-345541, a specific IKK inhibitor, increased TNFα killing in TNFα resistant tumor cell lines by increasing apoptosis, suggesting that inhibition of NF-κB may be an effective strategy to enhance the tumoricidal effects of TNFα.