Generation of Free Radicals by Emodic Acid and its [d-Lys6]GnRH-conjugate¶

Rahimipour, Shai; Bilkis, Izhak; Péron, Vincent; Gescheidt, Georg; Barbosa, Frédérique; Mazur, Yehuda; Koch, Yitzhak; Weiner, Lev; Fridkin, Mati

doi:10.1562/0031-8655(2001)074<0226:gofrbe>2.0.co;2

Cited by 23 publications

(8 citation statements)

References 54 publications

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“…Emodin has a structure similar to those of DMNQ and ubiquinone (shown in Fig. 12), but its capability to generate ROS has not been adequately studied (28), nor has a link between its anticancer effect and ROS generation been established. We found in the present study that emodin elicited an immediate elevation of cellular ROS level and a moderate reduction of the GSH/GSSG ratio.…”

Section: Discussionmentioning

confidence: 99%

Emodin Enhances Arsenic Trioxide-Induced Apoptosis via Generation of Reactive Oxygen Species and Inhibition of Survival Signaling

Yi¹,

Yang²,

et al. 2004

Cancer Research

147

123

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Although arsenic trioxide (As 2 O 3 ) induces apoptosis in a relatively wide spectrum of tumors, the sensitivity of different cell types to this treatment varies to a great extent. Because reactive oxygen species (ROS) are critically involved in As 2 O 3 -induced apoptosis, we attempted to explore the possibility that elevating the cellular ROS level might be an approach to facilitate As 2 O 3 -induced apoptosis. Emodin, a natural anthraquinone derivative, was selected because its semiquinone structure is likely to increase the generation of intracellular ROS. Its independent and synergistic effects with As 2 O 3 in cytotoxicity were studied, and the plausible signaling mechanism was investigated in HeLa cells. Cell Proliferation Assay and flow cytometry were used to assess cell viability and apoptosis. Electrophoretic mobility shift assay, luciferase reporter assay, and Western blotting were performed to analyze signaling alteration. The results demonstrated that coadministration of emodin, at low doses of 0.5-10 M, with As 2 O 3 enhanced As 2 O 3 -rendered cytotoxicity on tumor cells, whereas these treatments caused no detectable proproliferative or proapoptotic effects on nontumor cells. ROS generation was increased, and activation of nuclear factor B and activator protein 1 was suppressed by coadministration. All enhancements by emodin could be abolished by the antioxidant N-acetyl-L-cysteine. Therefore, we concluded that emodin sensitized HeLa cells to As 2 O 3 via generation of ROS and ROS-mediated inhibition on two major prosurvival transcription factors, nuclear factor B and activator protein 1. This result allows us to propose a novel strategy in chemotherapy that uses mild ROS generators to facilitate apoptosisinducing drugs whose efficacy depends on ROS.

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Section: Discussionmentioning

confidence: 99%

Emodin Enhances Arsenic Trioxide-Induced Apoptosis via Generation of Reactive Oxygen Species and Inhibition of Survival Signaling

Yi¹,

Yang²,

et al. 2004

Cancer Research

147

123

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“…It is appropriate to speculate the expansion-ROS generation by emodin, considering the structural characteristics of emodin. It being a quinone and an effective electron acceptor is likely that emodin intracellularly interacts with molecular oxygen and generates superoxide anion (39). There are several recent studies showing the ability of emodin to generate ROS in a variety of tumor cells (40 -45).…”

Section: Molecular Cancer Therapeutics 1695mentioning

confidence: 99%

Emodin azide methyl anthraquinone derivative triggers mitochondrial-dependent cell apoptosis involving in caspase-8-mediated Bid cleavage

Yan

Liang²,

Zhang³

et al. 2008

Molecular Cancer Therapeutics

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AMAD, an emodin azide methyl anthraquinone derivative, was extracted from the nature giant knotweed rhizome of traditional Chinese herbs. Here, we investigated the anticancer activities and signaling pathways implicated in AMAD-induced apoptosis in human breast cancer cell lines MDA-MB-453 and human lung adenocarcinoma Calu-3 cells. AMAD was found to have a potent cytotoxic effect on both cell lines. Hoechst 33258 staining and Annexin V/propidium iodide double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V -positive cells in a dose-dependent manner, respectively. Moreover, this apoptotic induction was associated with a collapse of the mitochondrial membrane potential and activated caspases (cysteine aspartase) cascade involving in caspase-8, caspase-9, caspase-3, and poly(ADP-ribose) polymerase cleavage in a concentration-dependent manner. It was noteworthy that AMAD also effectively cleaved Bid, a BH3 domaincontaining proapoptotic Bcl-2 family member, and induced the subsequent release of cytochrome c from mitochondria into the cytosol. Furthermore, suppression of caspase-8 activity with Z

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“…Emodin was chosen for study because it is a known redox effector capable of acting as a pro-oxidant and generating ROS. As an effective electron acceptor it can interact intracellularly with molecular oxygen to generate superoxide anion [18]. Emodin is a naturally occurring agent found in the roots and barks of certain plants, molds, lichens, and Chinese herbs [19].…”

Section: Introductionmentioning

confidence: 99%

Very low doses of ionizing radiation and redox associated modifiers affect survivin-associated changes in radiation sensitivity

Miller

Murley

Rademaker

et al. 2016

Free Radical Biology and Medicine

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Abstract:Exposure of cells to a dose of ionizing radiation as low as 5 mGy can induce changes in radiation sensitivity expressed by cells exposed to subsequent higher doses at later times. This is referred to as an adaptive effect. We describe a unique survivin-associated adaptive response in which increased radiation resistance or sensitization of cells can be induced by exposure to 5 mGy or to the free radical generating drug Emodin (1,3,8-trihydroxy-6-2 methylanthraquinone), a naturally occurring anthraquinone. The purpose of this study was to determine the role of free radical generating processes in affecting both the intracellular localization of the inhibitor of apoptosis protein survivin and its subsequent effect on radiation response in the presence or absence of the anti-oxidant N-acetyl-L-cysteine (NAC).Experiments were performed using two well characterized murine sarcomas: SA-NH p53 wildtype (WT) and FSa p53 mutant (Mut), grown either in culture or as solid tumors in the right hind legs of C3H mice. Doses of 5 mGy or 50 μM Emodin were used to induce changes in the response of these tumor cells to higher radiation exposures using a multi-dosing paradigm.Effects on radiation sensitivity were determined for SA-NH and FSa cells as a function of survivin translocation either to the cytoplasm or nucleus in the presence or absence of 10 mM NAC treatment. In vitro survival assays (2 Gy per fraction, two once daily fractions) and tumor growth delay (TGD) (5 Gy per fraction, five once daily fractions) studies were performed. Intracellular localization of survivin was determined by enzyme-linked immunosorbent assay (ELISA) and correlated to survival response and treatment conditions. 2 Gy alone had no effect on intracellular translocation of survivin. When preceded 15 min earlier by 5 mGy or Emodin exposures, survivin became elevated in the cytoplasm of p53 WT SA-NH as compared to the nuclei of p53 Mut FSa cells. SA-NH cells transfected with p53 small interfering RNA (siRNA), in contrast, responded similarly to p53 Mut FSa cells by becoming more radiation sensitive if exposed to 5 mGy prior to each 2 Gy irradiation. In contrast to their respective responses to five once daily 5 Gy fractions, SA-NH tumors were protected by 5 mGy exposures administered 15 min prior to each daily 5 Gy dose as evidenced by a more rapid growth (1.9 day decrease in TGD, P = 0.032), while FSa tumors were sensitized, growing at a much slower rate (4.5 day increase in TGD, P < 0.001). Exposure of SA-NH and FSa tumor cells to 10 mM NAC inhibited the ability of 5 mGy and Emodin to induce intracellular translocation of survivin and the corresponding altered adaptive survival response. The survivin-associated adaptive response can be induced following a multi-dosing scheme in which very low radiation doses are followed shortly thereafter by higher doses consistent with a standard image guided radiotherapy 3 protocol that is currently widely used in the treatment of cancer. While induced by exposure to free radical generating stresses, the ...

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Generation of Free Radicals by Emodic Acid and its [d-Lys6]GnRH-conjugate¶

Cited by 23 publications

References 54 publications

Emodin Enhances Arsenic Trioxide-Induced Apoptosis via Generation of Reactive Oxygen Species and Inhibition of Survival Signaling

Emodin Enhances Arsenic Trioxide-Induced Apoptosis via Generation of Reactive Oxygen Species and Inhibition of Survival Signaling

Emodin azide methyl anthraquinone derivative triggers mitochondrial-dependent cell apoptosis involving in caspase-8-mediated Bid cleavage

Very low doses of ionizing radiation and redox associated modifiers affect survivin-associated changes in radiation sensitivity

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