Synergistic effects of ascorbate and sorafenib in hepatocellular carcinoma: New insights into ascorbate cytotoxicity

Rouleau, Lauren; Antony, Anil Noronha; Bisetto, Sara; Newberg, Andrew; Doria, Cataldo; Levine, Mark; Monti, Daniel; Hoek, Jan B.

doi:10.1016/j.freeradbiomed.2016.03.031

Cited by 38 publications

(38 citation statements)

References 66 publications

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“…Previous studies have demonstrated that P-AscH − has synergistic or additive effects with many radio-chemotherapy regimens in cancer cells, and radio-protective effects in normal cells [17, 38–42]. Our current study extends these observations to clearly demonstrate the efficacy of P-AscH − in the hypoxic environment of PDAC.…”

Section: Discussionsupporting

confidence: 79%

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

Wilkes

O’Leary

et al. 2018

Clin Exp Metastasis

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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.

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Section: Discussionsupporting

confidence: 79%

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

Wilkes

O’Leary

et al. 2018

Clin Exp Metastasis

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“…25 , 26 We recently confirmed this previous work with a series of cell line experiments and also observed that ascorbate deregulates cellular calcium homeostasis, thereby promoting cell death. 27 There are also other proposed mechanisms of action. Ascorbate functions as a cofactor for a group of enzymes (Fe and 2-oxoglutarate-dependent dioxygenases) such as hypoxia inducible factor (HIF) hydroxylases, which affect HIF protein levels through marking HIF for proteosomal degradation and also cotranscription factor binding.…”

Section: Discussionmentioning

confidence: 99%

Retrospective Evaluation of Clinical Experience With Intravenous Ascorbic Acid in Patients With Cancer

et al. 2018

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Background. Intravenous ascorbic acid (IV AA) has been used extensively in cancer patients throughout the United States. Currently, there are limited data on the safety and clinical effects of IV AA. The purpose of this study was to expand the current literature using a retrospective analysis of adverse events and symptomatic changes of IV AA in a large sample of cancer patients. Methods. We conducted a retrospective chart review of all patients receiving IV AA for cancer at the Thomas Jefferson University Hospital over a 7-year period. We assessed all reports of adverse events, laboratory findings, and hospital or emergency department admissions. We also reviewed quality-of-life data, including fatigue, nausea, pain, appetite, and mood. Results. There were 86 patients who received a total of 3034 doses of IV AA ranging from 50 to 150g. In all, 32 patients received only ascorbic acid as part of their cancer management (1197 doses), whereas 54 patients received ascorbic acid in conjunction with chemotherapy (1837 doses). The most common adverse events related to ascorbic acid were temporary nausea and discomfort at the injection site. All events reported in the ascorbic acid alone group were associated with less than 3% of the total number of infusions. Patients, overall, reported improvements in fatigue, pain, and mood while receiving ascorbic acid. Conclusions. The results of this retrospective analysis support the growing evidence that IV AA is generally safe and well tolerated in patients with cancer, and may be useful in symptom management and improving quality of life.

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“…There are numerous studies that have demonstrated a cytotoxic effect of ascorbate on tumor cells in vitro , either alone or in combination with chemotherapeutics ( Wells et al, 1995 ; Reddy et al, 2001 ; Pathak et al, 2002 ; Wozniak and Anuszewska, 2002 ; Guerriero et al, 2006 ; Kassouf et al, 2006 ; Chen et al, 2007 , 2012 ; Martinotti et al, 2011 ; Verrax et al, 2011 ; Ma et al, 2014 ; Cieslak et al, 2015 ; Xia et al, 2017 ) or radiation ( Herst et al, 2012 ; Castro et al, 2014 ). The cytotoxicity in many of these studies reflects the oxidative stress resulting from the H 2 O 2 generated in cell culture medium when ascorbate is present at concentrations of 1 mM or above, and manifests as increased cell cycle arrest, p53 upregulation, decreased ATP levels, compromised mitochondrial function, suppression of antioxidant gene expression NrF-2 and/or cell death by apoptosis ( Tarumoto et al, 2004 ; Fromberg et al, 2011 ; Rouleau et al, 2016 ; Yang et al, 2017 ). Anti-cancer effects have also been demonstrated with ascorbate levels well below 1 mM: levels as low as 100 μM or even 1 μM in the culture medium enhanced the susceptibility of cancer cells to etoposide, cisplatin, or doxorubicin ( Kurbacher et al, 1996 ; Reddy et al, 2001 ; Tarumoto et al, 2004 ; An et al, 2011 ).…”

Section: Anti-cancer Activities Of Ascorbatementioning

confidence: 99%

Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence

2018

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Whether vitamin C (ascorbate) has a role to play as an anti-cancer agent has been debated for decades. Ascorbate has been used by cancer patients in an unregulated environment, either as a dietary supplement or in pharmacological doses administered by infusion, with numerous reports of clinical benefit, but in the absence of rigorous clinical trial data. The design of appropriate clinical trials has been hindered by a lack of understanding of the mechanism(s) of action that would inform the choice of effective dose, timing of administration and likely responsive cancer models. More recently, expanded understanding of the biological activities of ascorbate has led to a number of plausible hypotheses for mechanisms of anti-cancer activity. Prominent among these are the generation of significant quantities of hydrogen peroxide by the autoxidation of supra-physiological concentrations of ascorbate and stimulation of the 2-oxoglutarate-dependent dioxygenase family of enzymes (2-OGDDs) that have a cofactor requirement for ascorbate. Hydrogen peroxide generation is postulated to generate oxidative stress that preferentially targets cancer cells. The 2-OGDDs include the hydroxylases that regulate the hypoxic response, a major driver of tumor survival, angiogenesis, stem cell phenotype and metastasis, and the epigenetic histone and DNA demethylases. The latter are of particular interest, with recent studies suggesting a promising role for ascorbate in the regulation of the ten-eleven translocase (TET) DNA demethylases in hematological cancers. Support for these proposed mechanisms has come from many in vitro studies, and xenograft animal models have consistently shown an anti-cancer effect of ascorbate administration. However, decisive evidence for any particular mechanism(s) of action is not yet available from an in vivo setting. With a number of early phase clinical trials currently underway, evidence for potential mechanism(s) of action is required to inform the most appropriate study design and choice of cancer model. Hopefully such information will result in sound clinical data that will avert adding any further controversy to this already contentious debate.

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Synergistic effects of ascorbate and sorafenib in hepatocellular carcinoma: New insights into ascorbate cytotoxicity

Cited by 38 publications

References 66 publications

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

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

Retrospective Evaluation of Clinical Experience With Intravenous Ascorbic Acid in Patients With Cancer

Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence

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