Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy

Doskey, Claire M.; Buranasudja, Visarut; Wagner, Brett A.; Wilkes, Justin G.; Du, Juan; Cullen, Joseph J.; Buettner, Garry R.

doi:10.1016/j.redox.2016.10.010

Cited by 253 publications

(271 citation statements)

References 62 publications

Supporting

Mentioning

257

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, certain tumor cells have been found to be susceptible to H 2 O 2 toxicity [48]. Our present study clearly shows that ascorbic acid significantly increased (>75-fold) TPT cytotoxicity in MCF-7 breast cancer cells, and it was synergistic at all concentrations of TPT, especially at lower and biologically more relevant concentrations of TPT.…”

Section: Discussionsupporting

confidence: 68%

Synergistic enhancement of topotecan-induced cell death by ascorbic acid in human breast MCF-7 tumor cells

Sinha

Erve

Kumar

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

Topotecan, a derivative of camptothecin, is an important anticancer drug for the treatment of various human cancers in the clinic. While the principal mechanism of tumor cell killing by topotecan is due to its interactions with topoisomerase I, other mechanisms, e.g., oxidative stress induced by reactive free radicals, have also been proposed. However, very little is known about how topotecan induces free radical-dependent oxidative stress in tumor cells. In this report we describe the formation of a topotecan radical, catalyzed by a peroxidase-hydrogen peroxide system. While this topotecan radical did not undergo oxidation-reduction with molecular O2, it rapidly reacted with reduced glutathione and cysteine, regenerating topotecan and forming the corresponding glutathiyl and cysteiniyl radicals. Ascorbic acid, which produces hydrogen peroxide in tumor cells, significantly increased topotecan cytotoxicity in MCF-7 tumor cells. The presence of ascorbic acid also increased both topoisomerase I-dependent topotecan-induced DNA cleavage complex formation and topotecan-induced DNA double-strand breaks, suggesting that ascorbic acid participated in enhancing DNA damage induced by topotecan and that the enhanced DNA damage is responsible for the synergistic interactions of topotecan and ascorbic acid. Cell death by topotecan and the combination of topotecan and ascorbic acid was predominantly due to necrosis of MCF-7 breast tumor cells.

show abstract

Section: Discussionsupporting

confidence: 68%

Synergistic enhancement of topotecan-induced cell death by ascorbic acid in human breast MCF-7 tumor cells

Sinha

Erve

Kumar

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…The 5-year survival rate for localized RC is 90%; however, as RC spreads to regional lymph nodes or distant parts of the body, the 5-year survival rate drops to between 71% and 13% in the United States [1]. These malignancies are ascribed to accumulation of protein alterations, including dissemination of proto-oncogenes and loss or inactivation of tumor suppressor genes, which ultimately lead to tumor evolution and progression [2-6]. Furthermore, the increased survival and invasiveness of tumor cells are typical characteristics of RC [7, 8], suggesting a clinical need to abate excessive RC cell survival and migration.…”

Section: Introductionmentioning

confidence: 99%

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

Zhao

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The Hippo-Yap pathway is associated with tumor development and progression. However, little evidence is available concerning its role in cancer cell apoptosis and migration via mitochondrial homeostasis. Here, we identify mitochondrial fission as a regulator of the Hippo–Yap pathway in human rectal cancer tumorigenesis and metastasis. Methods: In this study, we performed loss-of function assays concerning Yap in RCC via shRNA. Cellular viability and apoptosis were measured via MTT, the TUNEL assay and trypan blue staining. Mitochondrial function was assessed via JC1 staining, the mPTP opening assay, mitochondrial respiratory function analysis, electron microscopy and immunofluorescence analysis of HtrA2/Omi. Mitophagy and mitochondrial fission were assessed via western blots and immunofluorescence. Cell migration was evaluated via the Transwell assay, wound-healing assay and immunofluorescence analysis of F-actin. The interaction between JNK and Yap was detected via co-immunoprecipitation and Yap recombinant mutagenic plasmid transfection. Western blots were used to analyze signaling pathways in conjunction with JNK inhibitors or HtrA2/Omi siRNA. Results: Yap is upregulated in human rectal cancer cells, where its expression correlates positively with cell survival and migration. Functional studies established that silencing of Yap drove JNK phosphorylation, which induced Drp1 activation and translocation to the surface of mitochondria, initiating mitochondrial fission. Excessive mitochondrial fission mediated HtrA2/Omi leakage from the mitochondria into the cytoplasm, where HtrA2/Omi triggered cellular apoptosis via the mitochondrial apoptosis pathway. Moreover, released HtrA2/Omi also phosphorylated cofilin and inhibited cofilin-mediated F-actin polymerization. F-actin collapse perturbed lamellipodia formation and therefore impaired cellular migration and invasion. Conclusion: Collectively, our results demonstrate that Hippo-Yap can serve as a tumor promoter in human rectal cancer and acts by restricting JNK/Drp1/mitochondrial fission/ HtrA2/Omi, with potential implications for new approaches to human rectal cancer therapy.

show abstract

“…Note that figures display P-AscH − dose in both molarity and on a mole cell − 1 basis. Recent studies have demonstrated that specifying the dose of xenobiotics, including P-AscH − , on a “mole per cell” basis results in improved correlations with toxicity markers as well as greater information content in experimental data [28, 29]. The doubling time of MIA PaCa-2 cells treated with P-AscH − was 59 ± 5 h versus 43 ± 0.2 h (means ± SEM, n = 3, p < 0.05) for controls when treated with the ED 50 dose, 7 mM (7 pmol cell − 1 ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…P-AscH − will increase extracellular H 2 O 2 , which is transported across the plasma membrane into cancer cells [18, 29, 34]. To determine whether the P-AscH − -induced HIF-1α suppression, VEGF suppression, and decreased clonogenic survival in hypoxia were due to H 2 O 2 , cells were co-treated with catalase (100 U/mL in the culture medium) or transfected with either a control adenoviral vector, AdGFP (50 MOI), or the adenoviral vector containing the catalase gene, AdCat (50 MOI), to increase intracellular catalase activity.…”

Section: Resultsmentioning

confidence: 99%

Pharmacologic ascorbate (P-AscH−) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma

Wilkes

O’Leary

et al. 2018

Clin Exp Metastasis

Self Cite

View full text Add to dashboard Cite

HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH−), induces cytotoxicity and oxidative stress selectively in cancer cells by acting as a pro-drug for the delivery of hydrogen peroxide (H2O2); early clinical data suggest improved survival and inhibition of metastasis in patients being actively treated with P-AscH−. Previous studies have demonstrated that activation of HIF-1α is necessary for P-AscH− sensitivity. We hypothesized that pancreatic cancer (PDAC) progression and metastasis could be be targeted by P-AscH− via H2O2-mediated inhibition of HIF-1α stabilization. Our study demonstrates an oxygen- and prolyl hydroxylase-independent regulation of HIF-1α by P-AscH−. Additionally, P-AscH− decreased VEGF secretion in a dose-dependent manner that was reversible with catalase, consistent with an H2O2-mediated mechanism. Pharmacological and genetic manipulations of HIF-1α did not alter P-AscH−-induced cytotoxicity. In vivo, P-AscH− inhibited tumor growth and VEGF expression. We conclude that P-AscH− suppresses the levels of HIF-1α protein in hypoxic conditions through a post-translational mechanism. These findings suggest potential new therapies specifically designed to inhibit the mechanisms that drive metastases as a part of PDAC treatment.

show abstract

Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy

Cited by 253 publications

References 62 publications

Synergistic enhancement of topotecan-induced cell death by ascorbic acid in human breast MCF-7 tumor cells

Synergistic enhancement of topotecan-induced cell death by ascorbic acid in human breast MCF-7 tumor cells

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

Pharmacologic ascorbate (P-AscH−) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma

Contact Info

Product

Resources

About