Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells.

Abstract

Aminoflavone (5-amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methylchromen-4-one; AF; NSC 686288), a novel anticancer candidate agent, is undergoing clinical evaluation. AF induces DNA-protein cross-links (DPCs), Gamma-H2AX phosphorylation, aryl hydrocarbon receptor (AhR) signaling, apoptosis and its own metabolism via cytochrome P4501A1 and 1A2 (CYP1A1/1A2) activation in sensitive estrogen receptor positive (ER+) MCF7 breast cancer cells. Estrogen receptor negative (ER-) breast cancer is typically more aggressive with a poorer prognosis. In this investigation, we evaluated the ability of AF to induce reactive oxygen species (ROS) formation, oxidative DNA damage and apoptosis in ER- MDA-MB-468 breast cancer cells. The antioxidant, N-acetyl-L-cysteine (NAC), attenuated the cytotoxic effects of AF in MDA-MB-468 cells; an effect is also observed in ER+ T47D breast cancer cells. Nonmalignant MCF10A breast epithelial cells were resistant to the cytotoxic effects of AF. AF increased intracellular ROS, an effect blocked by NAC and the CYP1A1/1A2 inhibitor, alpha-Naphthoflavone (alpha-NF). AF induced oxidative DNA damage as evidenced by increased 8-oxo-7,8-dihydroguanine (8-oxodG) levels and DPC formation in these cells. AF caused S-phase arrest corresponding to an increase in p21((waf1/cip1)) protein expression. AF induced caspase 3, 8 and 9 activation, caspase-dependent apoptotic body formation and poly [ADP-ribose] polymerase (PARP) cleavage. Pretreatment with the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp(OMe)-fluoromethylketone inhibited apoptosis and partially inhibited ROS formation and oxidative DNA damage. Pretreatment with NAC attenuated AF-induced apoptotic body formation and caspase 3 activation. These studies suggest AF inhibits the growth of breast cancer cells in part, by inducing ROS production, oxidative DNA damage and apoptosis and has the potential to treat hormone-independent breast cancer.

• Authors: Lancelot McLean, Ubaldo Soto, Keli Agama, Jawad Francis, Randi Jimenez, Yves Pommier, Lawrence Sowers, Eileen Brantley
• Journal: International journal of cancer (Int J Cancer) Vol. 122 Issue 7 Pg. 1665-74 (Apr 01 2008) ISSN: 1097-0215 [Electronic] United States
• PMID: 18059023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: (c) 2007 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• DNA, Neoplasm
• Flavonoids
• Free Radical Scavengers
• Reactive Oxygen Species
• Receptors, Estrogen
• aminoflavone
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1A2
• Caspases
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Antineoplastic Agents (antagonists & inhibitors, pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (chemistry, drug therapy, genetics, pathology)
• Caspases (metabolism)
• Cytochrome P-450 CYP1A1 (metabolism)
• Cytochrome P-450 CYP1A2 (metabolism)
• DNA Damage (drug effects)
• DNA, Neoplasm (drug effects)
• Enzyme Activation (drug effects)
• Female
• Flavonoids (antagonists & inhibitors, pharmacology)
• Free Radical Scavengers (pharmacology)
• Humans
• Reactive Oxygen Species (metabolism)
• Receptors, Estrogen (analysis)
• S Phase (drug effects)