NF-kappaB is involved in SHetA2 circumvention of TNF-alpha resistance, but not induction of intrinsic apoptosis.

Abstract

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-kappaB (NF-kappaB) is involved in SHetA2-regulated intrinsic and extrinsic apoptosis. SHetA2 inhibited basal and TNF-alpha-induced or hydrogen peroxide-induced NF-kappaB activity through counter-regulation of upstream kinase (IkappaB kinase) activity, inhibitor protein (IkappaB-alpha) phosphorylation, and p-65 NF-kappaB 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-kappaB repression is involved in SHetA2 circumvention of resistance to TNF-alpha-induced extrinsic apoptosis, but not in SHetA2 induction of intrinsic apoptosis.

• Authors: Shylet Chengedza, Doris Mangiaracina Benbrook
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 21 Issue 3 Pg. 297-305 (Mar 2010) ISSN: 1473-5741 [Electronic] England
• PMID: 20032777 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• (((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione
• Antineoplastic Agents
• Chromans
• NF-kappa B
• Thiones
• Tumor Necrosis Factor-alpha
• Hydrogen Peroxide
• I-kappa B Kinase

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Line, Tumor
• Chromans (therapeutic use)
• Drug Resistance, Neoplasm
• Female
• Humans
• Hydrogen Peroxide (pharmacology)
• I-kappa B Kinase (antagonists & inhibitors)
• NF-kappa B (metabolism)
• Ovarian Neoplasms (drug therapy, metabolism)
• Thiones (therapeutic use)
• Tumor Necrosis Factor-alpha (therapeutic use)