Novel 5-Aminoflavone Derivatives as Specific Antitumor Agents in Breast Cancer

Akama, Tsutomu; Shida, Yasushi; Sugaya, Toru; Ishida, Hiroyuki; Gomi, Katsushige; Kasai, Masaji

doi:10.1021/jm950938g

Cited by 86 publications

(79 citation statements)

References 38 publications

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“…AF induces DNA single-strand break formation, DNA-protein cross-link formation, cell cycle arrest, histone g-H2AX phosphorylation, CYP1A1 and CYP1A2 expression and its own metabolism in sensitive ER1 MCF-7 human breast cancer cells. [3][4][5][6]8 Stabilization of p53 and increased expression of p21 have also been shown to occur in MCF-7 cells treated with AF. 8,12 AF activates AhR signaling and induces apoptosis in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that its mechanism of action differs from that of anticancer agents currently used clinically, although the exact mechanism by which AF displays its anticancer activity has not been fully elucidated. [3][4][5][6] Previous studies indicate AF induces cytochromes P450 1A1 and 1A2 (CYP1A1/1A2) expression, DNA damage, cell cycle arrest and apoptosis in ER1 MCF-7 breast cancer cells. [7][8][9] AF activates the aryl hydrocarbon receptor (AhR) signaling pathway, which in turn leads to the transcriptional activation of genes such as CYP1A1 and CYP1A2 in MCF-7 cells which promote its metabolism.…”

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confidence: 99%

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

McLean

Soto

Agama

et al. 2008

Intl Journal of Cancer

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686288), a novel anticancer candidate agent, is undergoing clinical evaluation. AF induces DNA-protein cross-links (DPCs), c-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 (ER1) MCF7 breast cancer cells. Estrogen receptor negative (ER2) 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 ER2 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 ER1 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, a-Naphthoflavone (a-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. ' 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

McLean

Soto

Agama

et al. 2008

Intl Journal of Cancer

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“…COMPARE analyses revealing high Pearson correlation coefficients between DF 129, DF 203, DF 209 and DF 229 infer novel, but shared, biochemical mechanisms of action. In a recent publication, Akama et al (1996) reported the selective antiproliferative activity of 5-amino-2-(4-aminophenyl)-4H-1-benzopyran-4-one against MCF-7 cells. Intriguingly, the mechanism of action of this novel aminoflavone derivative, again not structurally dissimilar to the benzothiazoles reported in this paper, is not understood.…”

Section: Discussionmentioning

confidence: 99%

2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity

Bradshaw

Wrigley²,

Shi³

et al. 1998

Br J Cancer

216

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Summary 2-(4-Aminophenyl)benzothiazole (CJM 126) elicits biphasic growth-inhibitory effects against a panel of oestrogen receptor-positive (ER+) and oestrogen receptor-negative (ER-) human mammary carcinoma cell lines in vitro, yielding IC50 values in the nm range. Substitutions adjacent to the amino group in the 2-phenyl ring with a halogen atom or methyl group enhance potency in sensitive breast lines (pM IC50 values). Transient biphasic dose responses were induced but rapidly eradicated after specific drug exposure periods. Two human prostate carcinoma cell lines were refractory to the growth-inhibitory properties of 2-(4-aminophenyl)benzothiazoles; IC50 values > 30 ,UM were obtained.Potency and selectivity were confirmed when compounds were examined in the National Cancer Institute's Developmental Therapeutics screen; the spectrum of activity included specific ovarian, renal, colon as well as breast carcinoma cell lines. Moreover, comparing 6-day and 48-h incubations, the exposure time-dependent nature of the biphasic response was corroborated. Differential perturbation of cell cycle distribution followed treatment of MCF-7 and MDA 468 cells with substituted 2-(4-aminophenyl)benzothiazoles. In MDA 468 populations only, accumulation of events in G/M phase was observed. Two MCF-7 cell lines were established with acquired resistance to CJM 126 (IC50 values > 20 gM), which exhibit cross-resistance to substituted benzothiazoles, but equal sensitivity to tamoxifen and doxorubicin. Compared with standard anti-tumour agents evaluated in the National Cancer Institute in vitro cell panel, benzothiazoles revealed unique profiles of growth inhibition, suggesting a mode(s) of action shared with no known clinically active class of chemotherapeutic agents.

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“…Furthermore, flavonoids possess various pharmacological activities of inhibiting the activity of enzymes, antitumor, antibiosis, antivirus, anti-inflammatory and so on [3][4][5][6][7][8][9]. The potential treatment and prevention effects have been shown in degenerative diseases such as tumors, aging and cardiovascular diseases [10][11][12][13][14][15]. Additionally, some compounds of flavonoids possess potential application prospects as weak hormones at treating menopausal syndrome of women [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…The potential treatment and prevention effects have been shown in degenerative diseases such as tumors, aging and cardiovascular diseases [10][11][12][13][14][15]. Additionally, some compounds of flavonoids possess potential application prospects as weak hormones at treating menopausal syndrome of women [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Isolation and Structure Identification of Flavonoids

Feng¹,

Hao²,

Li³

2017

Flavonoids - From Biosynthesis to Human Health

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Flavonoids, which possess a basic C15 phenyl-benzopyrone skeleton, refer to a series of compounds in which two benzene rings (ring A and B) are connected to each other through three carbon atoms. Based on their core structure, flavonoids can be grouped into different flavonoid classes, such as flavonols, flavones, flavanones, flavanonols, anthocyanidins, isoflavones and chalcones. Flavonoids are often hydroxylated in positions 3, 5, 7, 3 0 ,4 0 and/or 5 0 . Frequently, one or more of these hydroxyl groups are methylated, acetylated, prenylated or sulfated. In plants, flavonoids are often present as O-or C-glycosides. The O-glycosides have sugar substituents bound to a hydroxyl group of the aglycone, usually located at position 3 or 7, whereas the C-glycosides have sugar groups bound to a carbon of the aglycone, usually 6-C or 8-C. The most common carbohydrates are rhamnose, glucose, galactose and arabinose. This chapter mainly introduces the methods of isolation and structure identification of flavonoids.

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Novel 5-Aminoflavone Derivatives as Specific Antitumor Agents in Breast Cancer

Cited by 86 publications

References 38 publications

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

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

2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity

Isolation and Structure Identification of Flavonoids

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