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Treatment of cancer with tumor necrosis factor-α (TNF-α) is hindered by resistance and toxicity. The flexible heteroarotinoid, SHetA2, sensitizes resistant ovarian cancer cells to TNF-α-induced extrinsic apoptosis, and also induces intrinsic apoptosis as a single agent. This study tested the hypothesis that nuclear factor-κB (NF-κB) is involved in SHetA2-regulated intrinsic and extrinsic apoptosis. SHetA2 inhibited basal and TNF-α-induced or hydrogen peroxide-induced NF-κB activity through counter-regulation of upstream kinase (IκB kinase) activity, inhibitor protein (IκB-α) phosphorylation, and p-65 NF-κB subunit nuclear translocation, but independently of reactive oxygen species generation. Ectopic over-expression of p-65, or treatment with TNF-α receptor 1 (TNFR1) small interfering RNA or a caspase-8 inhibitor, each attenuated synergistic apoptosis by SHetA2 and TNF-α, but did not affect intrinsic apoptosis caused by SHetA2. In conclusion, NF-κB repression is involved in SHetA2 circumvention of resistance to TNF-α-induced extrinsic apoptosis, but not in SHetA2 induction of intrinsic apoptosis.