The induction of oxidative stress and cellular death by the drinking water disinfection by-products, dichloroacetate and trichloroacetate in J774.A1 cells

Hassoun, Ezdihar A.; Ray, Sunetra

doi:10.1016/s1532-0456(03)00082-6

Cited by 30 publications

(44 citation statements)

References 20 publications

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“…1J). In addition to being a weak inhibitor of PDK, DCA also blocks glutathione S-transferase (21), inhibits cholesterol biosynthesis (22), promotes oxidative stress (23), and activates peroxisome proliferator-activated receptors (24). Both these published observations and our data persuaded us to use more specific strategies for implicating a role for PDH␣ phosphorylation in cancer biology.…”

Section: Resultsmentioning

confidence: 57%

Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

McFate

Mohyeldin

et al. 2008

Journal of Biological Chemistry

347

273

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High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase ␣ (PDH␣) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1␣ (HIF-1␣) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDH␣ phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1␣ expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.Cancer is a disease whereby genetic mutation results in uncontrolled cell growth combined with malignancy. High lactate accumulation, despite adequate oxygen availability, is a metabolic pattern commonly associated with malignant transformation of the uncontrolled dividing cell. This metabolic phenotype, termed aerobic glycolysis and historically known as the Warburg effect, is characterized by high glycolytic rates and reduced mitochondrial oxidation (1, 2), features that may favor cell survival in the hypoxic microenvironments found in tumors. This phenotype also favors the routing of key metabolic intermediates away from oxidative destruction and toward anabolic processes required by rapidly dividing cells (2). Hypoxia and growth factors may select for this phenotype by activating hypoxia-inducible transcription factor-1 (HIF-1), 3 which induces transcription of glucose transporters, glycolytic enzymes, and many other genes associated with hypoxic survival, angiogenesis, and tissue invasion (3). Hypoxia, HIF-1 activation, and high lactate levels in tumors are all independently correlated with poor clinical outcome for many human cancers (3-5). A causative role for hypoxia and HIF-1 stabilization in tumor formation and progression has been demonstrated (reviewed in Ref. 3). However, the buildup of glycoly...

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Section: Resultsmentioning

confidence: 57%

Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

McFate

Mohyeldin

et al. 2008

Journal of Biological Chemistry

347

273

View full text Add to dashboard Cite

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“…Therefore, an approximate effective minimal dose of DCA for these endometrial cell lines under the treatment period was determined to be between 5mM and 10mM. This DCA dose concentration and treatment time is within the effective range of previously published in vitro experiments (21). A statistically significant increase in viability was observed with HEC1A, HEC1B, and KLE with increasing DCA concentrations (p < 0.02).…”

Section: Dca Reduces Endometrial Cancer Cell Viability In a Dose-depementioning

confidence: 66%

Dichloroacetate induces apoptosis in endometrial cancer cells

Wong

Huggins

Debidda

et al. 2008

Gynecologic Oncology

189

170

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Purpose-A recent landmark study demonstrated that Dichloroacetate (DCA) treatment promoted apoptosis in lung, breast, and glioblastoma cancer cell lines by shifting metabolism from aerobic glycolysis to glucose oxidation coupled with NFAT-Kv1.5 axis remodeling. The objective of this study was to determine whether DCA induces apoptosis in endometrial cancer cells and to assess apoptotic mechanism.Methods-A panel of endometrial cancer cell lines with varying degrees of differentiation was treated with DCA and analyzed for apoptosis via flow cytometry. Biological correlates such as gene expression, intracellular Ca 2+ , and mitochondrial membrane potential were examined to assess apoptotic mechanism.Results-Initiation of apoptosis was observed in five low to moderately invasive cancer cell lines including Ishikawa, RL95-2, KLE, AN3CA, and SKUT1B while treatment had no effect on noncancerous 293T cells. Two highly invasive endometrial adenocarcinoma cell lines, HEC1A and HEC1B, were found to be resistant to DCA induced apoptosis. Apoptotic responding cell lines had a significant increase in early and late apoptotis, a decrease in mitochondrial membrane potential, and decreased Survivin transcript abundance, which are consistent with a mitochondrial-regulated mechanism. DCA treatment decreased intracellular calcium levels in most apoptotic responding cell lines which suggests a contribution from the NFAT-Kv1.5-mediated pathway. DCA treatment increased p53 upregulated modulator of apoptosis (PUMA) transcripts in cell lines with an apoptotic response, suggesting involvement of a p53-PUMA-mediated mechanism. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of Interest Statement:The authors declare there are no conflicts of interest. NIH Public Access

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“…Approximately 10%, 18%, 60%, and 80% of embryos developed edema after treatment with 4,8,16, and 32 mM of DCA, respectively by 144 hpf. Also, the extent of yolk sac edema was the highest among embryos treated with 16-32 mM of DCA by 144 hpf (Figure 1).…”

Section: Yolk Sac Edemamentioning

confidence: 99%

Dichloroacetate‐induced developmental toxicity and production of reactive oxygen species in zebrafish embryos

Hassoun

Kariya

Williams

2005

J Biochem & Molecular Tox

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Dichloroacetate (DCA) is one of the toxic by products that are formed during the chlorine disinfection process of drinking water. In this study, the developmental toxicity of DCA has been determined in zebrafish (Danio rerio) embryos. Embryos were exposed to different concentrations (4, 8, 16, and 32 mM) of the compound at the 4 h postfertilization (hpf) stage of development, and were observed for different developmental toxic effects at 8, 24, 32, 55, 80, and 144 hpf. Exposure of embryos to 8-32 mM of DCA resulted in significant increases in the heart rate and blood flow of the 55 and 80 hpf embryos that turned into significant decreases at the 144 hpf time point. At 144 hpf, malformations of mouth structure, notochord bending, yolk sac edema and behavioral effects including perturbed swimming and feeding behaviors were also observed. DCA was also found to produce time- and concentration-dependent increases in embryonic levels of superoxide anion (O2*-) and nitric oxide (NO), at various stages of development. The results of the study suggest that DCA-induced developmental toxic effects in zebrafish embryos are associated with production of reactive oxygen species in those embryos.

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The induction of oxidative stress and cellular death by the drinking water disinfection by-products, dichloroacetate and trichloroacetate in J774.A1 cells

Cited by 30 publications

References 20 publications

Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

Dichloroacetate induces apoptosis in endometrial cancer cells

Dichloroacetate‐induced developmental toxicity and production of reactive oxygen species in zebrafish embryos

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