(−)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: Role of topoisomerase IIα inhibition and reactive oxygen species

Takeda, Shuso; Noguchi, Momoko; Matsuo, Kyohei; Yamaguchi, Yasuhiro; Kudo, Taichi; Nishimura, Hajime; Okamoto, Yoshiharu; Amamoto, Toshiaki; Shindo, Mitsuru; Omiecinski, Curtis J.; Aramaki, Hironori

doi:10.1016/j.tox.2012.12.019

Cited by 26 publications

(62 citation statements)

References 40 publications

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“…These synthesized compounds were purified by HPLC (Highperformance liquid chromatography) or column chromatography, and their purity (> 98%) was confirmed by 1 H-and 13 C-NMR (Nuclear Magnetic Resonance) spectroscopy. No ring-opened derivatives of the xanthanolides' lactones were detected in these analyses (Takeda et al, 2011(Takeda et al, , 2013a. 2',7'-Dichlorofluorescein diacetate (DCFH-DA) and etoposide were purchased from Sigma Co. (St. Louis, MO, USA).…”

Section: Reagentsmentioning

confidence: 99%

“…L-Buthionine-sulfoximine (BSO) was purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). (Takeda et al, 2011(Takeda et al, , 2013a.…”

Section: Reagentsmentioning

confidence: 99%

“…Whole cell extracts were prepared as previously described (Takeda et al, 2013a). SDS-polyacrylamide gel electrophoresis/Western blot analysis was performed based on procedures described previously (Takeda et al, 2009(Takeda et al, , 2013a.…”

Section: Antibodies and Western Blot Analysismentioning

confidence: 99%

“…Cellular ROS levels were quantified according to reported methods using a DCFH-DA probe (LeBel et al, 1992;Takeda et al, 2013a).…”

Section: Ros Detectionmentioning

confidence: 99%

“…1), one of the major xanthanolides present in Xanthium strumarium (the Cocklebur plant), possessed potent anti-proliferative activity in breast cancer cells including the highly invasive human MDA-MB-231, which appeared to be mediated through the selective inhibition of Topoisomerase IIα (Topo IIα) and continuous production of reactive oxygen species (ROS), leading to the induction of GADD45γ tumor suppressor (Takeda et al, 2013a). Thus, ROS-mediated oxidative stress may participate in the biological activities of (-)-xanthatin.…”

Section: Introductionmentioning

confidence: 99%

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(–)-Xanthatin induces the prolonged expression of c-Fos through an <i>N</i>-acetyl-L-cysteine (NAC)-sensitive mechanism in human breast cancer MDA-MB-231 cells

et al. 2013

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-We reported that (-)-xanthatin, a xanthanolide sesquiterpene lactone present in the Cocklebur plant, exhibited potent anti-proliferative effects on human breast cancer cells, in which GADD45γ, a novel tumor suppressor gene, was induced. Mechanistically, topoisomerase IIα (Topo IIα) inhibition by (-)-xanthatin was shown to be the upstream trigger that stimulated the expression of GADD45γ mRNA and concomitantly produced reactive oxygen species (ROS) to maintain this expression. Since the anticancer drug etoposide, a selective Topo IIα inhibitor, has also been shown to induce intracellular ROS, (-)-xanthatin may exert its anti-proliferative effects on cancer cells in a similar manner to those of etoposide. In the present study, to generalize its applicability to cancer therapy, we further investigated the biological activities of (-)-xanthatin by comparing its activities to those of the established anti-cancer drug etoposide. After the exposure of breast cancer cells to (-)-xanthatin or etoposide, a prolonged and marked up-regulation in the expression of c-fos, a proapoptotic molecule, was detected together with GADD45γ; and the expression of these molecules was stabilized by ROS and abrogated by the pretreatment with N-acetyl-L-cysteine (NAC), a potent ROS scavenger. (-)-Xanthatin in particular exhibited stronger antiproliferative potential than that of etoposide, which underlies the marked induction of c-fos/GADD45γ and ROS production.

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Section: Reagentsmentioning

confidence: 99%

“…L-Buthionine-sulfoximine (BSO) was purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). (Takeda et al, 2011(Takeda et al, , 2013a.…”

Section: Reagentsmentioning

confidence: 99%

Section: Antibodies and Western Blot Analysismentioning

confidence: 99%

“…Cellular ROS levels were quantified according to reported methods using a DCFH-DA probe (LeBel et al, 1992;Takeda et al, 2013a).…”

Section: Ros Detectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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(–)-Xanthatin induces the prolonged expression of c-Fos through an <i>N</i>-acetyl-L-cysteine (NAC)-sensitive mechanism in human breast cancer MDA-MB-231 cells

et al. 2013

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Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: A mechanism for cancer chemopreventive action

Khan

Zubair

Faisal

et al. 2013

Molecular Nutrition Food Res

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Scope: Anticancer polyphenolic nutraceuticals from fruits, vegetables, and spices are generally recognized as antioxidants, but can be prooxidants in the presence of copper ions. We earlier proposed a mechanism for such activity of polyphenols and now we provide data in multiple cancer cell lines in support of our hypothesis. Methods and results: Through multiple assays, we show that polyphenols luteolin, apigenin, epigallocatechin-3-gallate, and resveratrol are able to inhibit cell proliferation and induce apoptosis in different cancer cell lines. Such cell death is prevented to a significant extent by cuprous chelator neocuproine and reactive oxygen species scavengers. We also show that normal breast epithelial cells, cultured in a medium supplemented with copper, become sensitized to polyphenol-induced growth inhibition. Conclusion: Since the concentration of copper is significantly elevated in cancer cells, our results strengthen the idea that an important anticancer mechanism of plant polyphenols is mediated through intracellular copper mobilization and reactive oxygen species generation leading to cancer cell death. Moreover, this prooxidant chemopreventive mechanism appears to be a mechanism common to several polyphenols with diverse chemical structures and explains the preferential cytotoxicity of these compounds toward cancer cells.

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The antitumour growth and antiangiogenesis effects of xanthatin in murine glioma dynamically evaluated by dynamic contrast‐enhanced magnetic resonance imaging

Wei

et al. 2018

Phytotherapy Research

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To investigate the suppressive effects of xanthatin on glioma growth in a nude mouse xenograft model and rat orthotopic implantation model using magnetic resonance imaging (MRI) to dynamically monitor the antitumour growth and antiangiogenesis effects of xanthatin. The nude mouse xenograft tumour model and rat orthotopic implantation model were established to observe the antitumour effects of xanthatin in vivo. In the rat orthotopic implanted tumour model, MRI scanning was used to dynamically monitor the antitumour growth effect and evaluate the antiangiogenesis effect of xanthatin. We found that xanthatin at a dose of 0.4 mg/10 g dramatically decreased the growth of xenograft tumours in nude mice. The antiangiogenesis effect of xanthatin C6 glioma was evaluated by dynamic contrast-enhanced (DCE) MRI via comparison of the volume transfer constant (K trans ) value, a parameter that reflects vessel permeability. We found that xanthatin at the doses of 8 and 16 mg/kg significantly decreased the K trans value, which suggests that xanthatin has antiangiogenesis effects. These data demonstrate the suppressive effects of xanthatin on C6 glioma occur via antiangiogenesis. Meanwhile, this study also provides evidence for the application of quantitative parameters of DCE-MRI for dynamically evaluating the growth and angiogenesis of intracranial tumours and for experimental and clinical research.

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(−)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: Role of topoisomerase IIα inhibition and reactive oxygen species

Cited by 26 publications

References 40 publications

(–)-Xanthatin induces the prolonged expression of c-Fos through an <i>N</i>-acetyl-L-cysteine (NAC)-sensitive mechanism in human breast cancer MDA-MB-231 cells

(–)-Xanthatin induces the prolonged expression of c-Fos through an <i>N</i>-acetyl-L-cysteine (NAC)-sensitive mechanism in human breast cancer MDA-MB-231 cells

Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: A mechanism for cancer chemopreventive action

The antitumour growth and antiangiogenesis effects of xanthatin in murine glioma dynamically evaluated by dynamic contrast‐enhanced magnetic resonance imaging

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