NF-κB is involved in SHetA2 circumvention of TNF-α resistance, but not induction of intrinsic apoptosis

Treatment of cancer with tumor necrosis factor-alpha (TNF-alpha) is hindered by resistance and toxicity. The flexible heteroarotinoid, SHetA2, sensitizes resistant ovarian cancer cells to TNF-alpha-induced extrinsic apoptosis, and also induces intrinsic apoptosis as a single agent. This study tested the hypothesis that nuclear factor-kappa B (NF-kappa B) is involved in SHetA2-regulated intrinsic and extrinsic apoptosis. SHetA2 inhibited basal and TNF-alpha-induced or hydrogen peroxide-induced NF-kappa B activity through counter-regulation of upstream kinase (I kappa B kinase) activity, inhibitor protein (I kappa B-alpha) phosphorylation, and p-65 NF-kappa B subunit nuclear translocation, but independently of reactive oxygen species generation. Ectopic over-expression of p-65, or treatment with TNF-alpha receptor 1 (TNFR1) small interfering RNA or a caspase-8 inhibitor, each attenuated synergistic apoptosis by SHetA2 and TNF-alpha, but did not affect intrinsic apoptosis caused by SHetA2. In conclusion, NF-kappa B repression is involved in SHetA2 circumvention of resistance to TNF-alpha-induced extrinsic apoptosis, but not in SHetA2 induction of intrinsic apoptosis. Anti-Cancer Drugs 21: 297-305 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.