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

Lancelot McLean, Ubaldo Soto, Keli Agama, Jawad Francis, Randi Jimenez, Yves Pommier, Lawrence Sowers, Eileen Brantley

Research output: Contribution to journalArticle

51 Citations (Scopus)

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), γ-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, α-Naphthoflavone (α-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, benzyloxy-carbonyl-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.

Original languageEnglish (US)
Pages (from-to)1665-1674
Number of pages10
JournalInternational Journal of Cancer
Volume122
Issue number7
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

Fingerprint

aminoflavone
DNA Damage
Apoptosis
Breast Neoplasms
Reactive Oxygen Species
Acetylcysteine
Estrogen Receptors
Cytochromes
Caspase 3
Aryl Hydrocarbon Receptors
Caspase Inhibitors
Poly(ADP-ribose) Polymerases
Caspase 9
Caspase 8
Caspases
S Phase
Antineoplastic Agents
Breast
Antioxidants
Epithelial Cells

Keywords

  • Aminoflavone
  • Apoptosis
  • Breast cancer
  • DNA damage
  • Oxidative stress

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

McLean, L., Soto, U., Agama, K., Francis, J., Jimenez, R., Pommier, Y., ... Brantley, E. (2008). Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells. International Journal of Cancer, 122(7), 1665-1674. https://doi.org/10.1002/ijc.23244

Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells. / McLean, Lancelot; Soto, Ubaldo; Agama, Keli; Francis, Jawad; Jimenez, Randi; Pommier, Yves; Sowers, Lawrence; Brantley, Eileen.

In: International Journal of Cancer, Vol. 122, No. 7, 01.04.2008, p. 1665-1674.

Research output: Contribution to journalArticle

McLean, Lancelot ; Soto, Ubaldo ; Agama, Keli ; Francis, Jawad ; Jimenez, Randi ; Pommier, Yves ; Sowers, Lawrence ; Brantley, Eileen. / Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells. In: International Journal of Cancer. 2008 ; Vol. 122, No. 7. pp. 1665-1674.
@article{1bc0fddf381849ddbf1981db727fe622,
title = "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), γ-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, α-Naphthoflavone (α-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, benzyloxy-carbonyl-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.",
keywords = "Aminoflavone, Apoptosis, Breast cancer, DNA damage, Oxidative stress",
author = "Lancelot McLean and Ubaldo Soto and Keli Agama and Jawad Francis and Randi Jimenez and Yves Pommier and Lawrence Sowers and Eileen Brantley",
year = "2008",
month = "4",
day = "1",
doi = "10.1002/ijc.23244",
language = "English (US)",
volume = "122",
pages = "1665--1674",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "7",

}

TY - JOUR

T1 - Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells

AU - McLean, Lancelot

AU - Soto, Ubaldo

AU - Agama, Keli

AU - Francis, Jawad

AU - Jimenez, Randi

AU - Pommier, Yves

AU - Sowers, Lawrence

AU - Brantley, Eileen

PY - 2008/4/1

Y1 - 2008/4/1

N2 - 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), γ-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, α-Naphthoflavone (α-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, benzyloxy-carbonyl-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.

AB - 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), γ-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, α-Naphthoflavone (α-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, benzyloxy-carbonyl-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.

KW - Aminoflavone

KW - Apoptosis

KW - Breast cancer

KW - DNA damage

KW - Oxidative stress

UR - http://www.scopus.com/inward/record.url?scp=39649102145&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39649102145&partnerID=8YFLogxK

U2 - 10.1002/ijc.23244

DO - 10.1002/ijc.23244

M3 - Article

VL - 122

SP - 1665

EP - 1674

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 7

ER -