Curcumin‐induced GADD153 upregulation: Modulation by glutathione

Scott, David W.; Loo, George

doi:10.1002/jcb.21179

Cited by 25 publications

(21 citation statements)

References 42 publications

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“…Low levels of GSH have been found to decrease resistance of cancer cells to chemotherapeutic drugs [43], boost cell apoptosis [44] and mediate ROS-induced mitochondrial damage [45]. Without knowing the precise site of action, curcumin treatment was associated with decreased intracellular GSH which may account for its pro-apoptotic effects [46] but is inconsistent with the observed anti-oxidant properties of curcumin [47]. Recently, it has been convincingly shown that a number of flavonoids can induce GSH depletion in human tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Curcumin Inhibits Glyoxalase 1—A Possible Link to Its Anti-Inflammatory and Anti-Tumor Activity

et al. 2008

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BackgroundGlyoxalases (Glo1 and Glo2) are involved in the glycolytic pathway by detoxifying the reactive methylglyoxal (MGO) into D-lactate in a two-step reaction using glutathione (GSH) as cofactor. Inhibitors of glyoxalases are considered as anti-inflammatory and anti-carcinogenic agents. The recent finding that various polyphenols modulate Glo1 activity has prompted us to assess curcumin's potency as an Glo1 inhibitor.Methodology/Principal FindingsCultures of whole blood cells and tumor cell lines (PC-3, JIM-1, MDA-MD 231 and 1321N1) were set up to investigate the effect of selected polyphenols, including curcumin, on the LPS-induced cytokine production (cytometric bead-based array), cell proliferation (WST-1 assay), cytosolic Glo1 and Glo2 enzymatic activity, apoptosis/necrosis (annexin V-FITC/propidium iodide staining; flow cytometric analysis) as well as GSH and ATP content. Results of enzyme kinetics revealed that curcumin, compared to the polyphenols quercetin, myricetin, kaempferol, luteolin and rutin, elicited a stronger competitive inhibitory effect on Glo1 (Ki = 5.1±1.4 µM). Applying a whole blood assay, IC50 values of pro-inflammatory cytokine release (TNF-α, IL-6, IL-8, IL-1β) were found to be positively correlated with the Ki-values of the aforementioned polyphenols. Moreover, whereas curcumin was found to hamper the growth of breast cancer (JIMT-1, MDA-MB-231), prostate cancer PC-3 and brain astrocytoma 1321N1 cells, no effect on growth or vitality of human primary hepatocytes was elucidated. Curcumin decreased D-lactate release by tumor cells, another clue for inhibition of intracellular Glo1.Conclusions/SignificanceThe results described herein provide new insights into curcumin's biological activities as they indicate that inhibition of Glo1 by curcumin may result in non-tolerable levels of MGO and GSH, which, in turn, modulate various metabolic cellular pathways including depletion of cellular ATP and GSH content. This may account for curcumin's potency as an anti-inflammatory and anti-tumor agent. The findings support the use of curcumin as a potential therapeutic agent.

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Section: Discussionmentioning

confidence: 99%

Curcumin Inhibits Glyoxalase 1—A Possible Link to Its Anti-Inflammatory and Anti-Tumor Activity

et al. 2008

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“…Moreover, all stimulation of mRNA and protein expressions of CHOP and DR5 was almost completely abrogated by NAC (a ROS scavenger) but only partial reduced by BAPTA (a calcium chelator). In this aspect, previous studies showed that ROS is a molecular mediator inducing CHOP (31,32,46) and DR5 (10, 11, 47) expression.…”

Section: Discussionmentioning

confidence: 92%

15-deoxy-Δ12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: involvement of reactive oxygen species and C/EBP homologous transcription factor gene transcription

Chi

Huang

et al. 2008

Molecular Cancer Therapeutics

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Although 15-deoxy-# 12,14 -prostaglandin J 2 (15dPGJ 2 ) was reported to up-regulate death receptor 5 (DR5) protein expression and sensitize TRAIL-induced cytotoxicity, its action mechanism remains unclear. Using HCT116 colon cancer cells, we found that sensitization of TRAIL-induced cytotoxicity by 15dPGJ 2 resulted from up-regulation of DR5 via gene transcription but was not associated with PPAR-; activation. Moreover, 15dPGJ 2 induced GRP78, XBP1, and C/EBP homologous transcription factor (CHOP) expression in HCT116 cells, confirming that 15dPGJ 2 is an endoplasmic reticulum stress inducer. Knockdown of the CHOP gene by siRNA attenuated DR5 up-regulation and the sensitized cytotoxicity in colon cancer HCT116 and SW480. With deletion plasmids of DR5 promoters, we found that the CHOP-binding site was involved in activating the DR5 gene by 15dPGJ 2 . A mechanistic study showed the contributions of reactive oxygen species (ROS) and intracellular calcium in CHOP and DR5 gene up-regulation. 15dPGJ 2 was also found to induce DR5 in two prostate cancer cell lines, LNCaP and PC3. Although in LNCaP DR5 up-regulation was accompanied by CHOP expression by 15dPGJ 2 , no significant increase in CHOP expression or DR5 promoter activity was observed in PC3 cells. Intriguingly, 15dPGJ 2 induced ROS and calcium production in PC3 cells. This inability to induce CHOP was not due to the p53-null in PC3 cells, as similar extents of increase in CHOP protein were found due to 15dPGJ 2 in both wild-type and p53-null HCT116 cells. In summary, the effect of up-regulation of DR5 by 15dPGJ 2 in colon cancer cells is independent of PPAR-; and p53 but relies on CHOP induction through gene transcription involving ROS and calcium. [Mol Cancer Ther 2008;7(10):3429 -40]

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“…More recently, other results support the view that curcumin-induced GADD153 gene up-regulation is modulated by ROS generation through the ability of curcumin to neutralize glutathione. Moreover, some involvement of PI3K and PKCd, key parts of an important thiol redox-sensitive cascade, has been also suggested [142].…”

Section: Effects On Signal Transduction Pathwaysmentioning

confidence: 98%

New mechanisms and therapeutic potential of curcumin for colorectal cancer

Villegas

Sánchez-Fidalgo

Lastra

2008

Molecular Nutrition Food Res

119

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Curcumin is a polyphenol derived from Curcuma longa. Over the last few years, a number of studies have provided evidence of its main pharmacological properties including chemosensitizing, radiosensitizing, wound healing activities, antimicrobial, antiviral, antifungical, immunomodulatory, antioxidant and anti-inflammatory. More recent data provide interesting insights into the effect of this compound on cancer chemoprevention and chemotherapy. In fact, preclinical studies have shown its ability to inhibit carcinogenesis in various types of cancer including colorectal cancer (CRC). Curcumin has the capacity of interact with multiple molecular targets affecting the multistep process of carcinogenesis. Also, curcumin is able to arrest the cell cycle, to inhibit the inflammatory response and the oxidative stress and to induce apoptosis in cancer cells. Likewise, it has been shown to possess marked antiangiogenic properties. Furthermore, curcumin potentiates the growth inhibitory effect of cyclo-oxygenase (COX)-2 inhibitors and traditional chemotherapy agents implicating another promising therapy regimen in the future treatment of CRC. However, its clinical advance has been hindered by its short biological half-life and low bioavailability after oral administration. This review is intended to provide the reader an update of the bioavailability and pharmacokinetics of curcumin and describes the recently identified molecular pathways responsible of its anticancer potential in CRC.

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Curcumin‐induced GADD153 upregulation: Modulation by glutathione

Cited by 25 publications

References 42 publications

Curcumin Inhibits Glyoxalase 1—A Possible Link to Its Anti-Inflammatory and Anti-Tumor Activity

Curcumin Inhibits Glyoxalase 1—A Possible Link to Its Anti-Inflammatory and Anti-Tumor Activity

15-deoxy-Δ12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: involvement of reactive oxygen species and C/EBP homologous transcription factor gene transcription

New mechanisms and therapeutic potential of curcumin for colorectal cancer

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