Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models

Chen, Ping; Stone, Jennifer; Sullivan, Garrett G; Drisko, Jeanne; Chen, Qi

doi:10.1016/j.freeradbiomed.2011.05.031

Cited by 47 publications

(49 citation statements)

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“…Previous studies also reported that AA inhibited the growth of two NSCLC lines. The 48 h IC 50 for A549 was ∼2 mM [47] whereas the IC 50 for H1299 was >20 mM [48]. The previous results with A549 are very similar to our findings; however, our results indicate that H1299 is much more sensitive to AA treatment than found by Chen et al [48].…”

Section: Discussionsupporting

confidence: 87%

“…This is consistent with previous studies that showed normal human cell lines were much more tolerant to AA treatment compared to most cancer cell lines [48]. The IC 50 values for a 24 h treatment of the NSCLC cell lines were very similar or lower than the IC 50 values previously determined for human cancer cell lines representing a significant number of cancer types including leukemia, pancreatic, ovarian, breast, cervical, uterine, bladder, prostate, mesothelioma, liver, colon, gastric, renal, melanoma, glioblastoma, neuroblastoma, and lymphoma [31], [35], [38], [41], [47]–[50], [52]–[55]. Previous studies also reported that AA inhibited the growth of two NSCLC lines.…”

Section: Discussionsupporting

confidence: 66%

“…More recently, it has become clear that parenteral administration of AA results in much higher therapeutic doses than can be achieved using the oral administration methods utilized in these earlier clinical trials [23], [34], [46] and that these doses are effective alone or in combination with other anticancer agents in inducing cell death in several in vitro and in vivo cancer models [13], [29], [47]–[51]. Moreover, it has been shown that pharmacologic doses of AA exert effects through an extracellular autooxidation mechanism involving the ascorbyl radical and the subsequent generation of H 2 O 2 [33]–[35] rather than conversion to dehydroascorbic acid.…”

Section: Discussionmentioning

confidence: 99%

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Ascorbic Acid and a Cytostatic Inhibitor of Glycolysis Synergistically Induce Apoptosis in Non-Small Cell Lung Cancer Cells

et al. 2013

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Ascorbic acid (AA) exhibits significant anticancer activity at pharmacologic doses achievable by parenteral administration that have minimal effects on normal cells. Thus, AA has potential uses as a chemotherapeutic agent alone or in combination with other therapeutics that specifically target cancer-cell metabolism. We compared the effects of AA and combinations of AA with the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO) on the viability of three non-small cell lung cancer (NSCLC) cell lines to the effects on an immortalized lung epithelial cell line. AA concentrations of 0.5 to 5 mM caused a complete loss of viability in all NSCLC lines compared to a <10% loss of viability in the lung epithelial cell line. Combinations of AA and 3-PO synergistically enhanced cell death in all NSCLC cell lines at concentrations well below the IC50 concentrations for each compound alone. A synergistic interaction was not observed in combination treatments of lung epithelial cells and combination treatments that caused a complete loss of viability in NSCLC cells had modest effects on normal lung cell viability and reactive oxygen species (ROS) levels. Combination treatments induced dramatically higher ROS levels compared to treatment with AA and 3-PO alone in NSCLC cells and combination-induced cell death was inhibited by addition of catalase to the medium. Analyses of DNA fragmentation, poly (ADP-ribose) polymerase cleavage, annexin V-binding, and caspase activity demonstrated that AA-induced cell death is caused via the activation of apoptosis and that the combination treatments caused a synergistic induction of apoptosis. These results demonstrate the effectiveness of AA against NSCLC cells and that combinations of AA with 3-PO synergistically induce apoptosis via a ROS-dependent mechanism. These results support further evaluation of pharmacologic concentrations of AA as an adjuvant treatment for NSCLC and that combination of AA with glycolysis inhibitors may be a promising therapy for the treatment of NSCLC.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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Ascorbic Acid and a Cytostatic Inhibitor of Glycolysis Synergistically Induce Apoptosis in Non-Small Cell Lung Cancer Cells

et al. 2013

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“…Therefore, the potential interaction between them might warrant additional study. Parenteral glutathione is another alternative therapy frequently used in conjunction with pharmacologic ascorbate that interferes with ascorbatemediated cytotoxicity (15).…”

Section: Safetymentioning

confidence: 99%

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

Parrow

Leshin

Levine

2013

Antioxidants & Redox Signaling

110

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Significance: Ewan Cameron reported that ascorbate, given orally and intravenously at doses of up to 10 g/day, was effective in the treatment of cancer. Double-blind placebo-controlled clinical trials showed no survival advantage when the same doses of ascorbate were given orally, leading the medical and scientific communities to dismiss the use of ascorbate as a potential cancer treatment. However, the route of administration results in major differences in ascorbate bioavailability. Tissue and plasma concentrations are tightly controlled in response to oral administration, but this can be bypassed by intravenous administration. These data provide a plausible scientific rationale for the absence of a response to orally administered ascorbate in the Mayo clinic trials and indicate the need to reassess ascorbate as a cancer therapeutic. Recent Advances: High dose ascorbate is selectively cytotoxic to cancer cell lines through the generation of extracellular hydrogen peroxide (H 2 O 2 ). Murine xenograft models confirm a growth inhibitory effect of pharmacological concentrations. The safety of intravenous ascorbate has been verified in encouraging pilot clinical studies. Critical Issues: Neither the selective toxicity of pharmacologic ascorbate against cancer cells nor the mechanism of H 2 O 2 -mediated cytotoxicity is fully understood. Despite promising preclinical data, the question of clinical efficacy remains. Future Directions: A full delineation of mechanism is of interest because it may indicate susceptible cancer types. Effects of pharmacologic ascorbate used in combination with standard treatments need to be defined. Most importantly, the clinical efficacy of ascorbate needs to be reassessed using proper dosing, route of administration, and controls.

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“…v) Levine and coworkers have demonstrated that pharmacologic AA concentrations achievable through intravenous administration were cytotoxic to many types of cancer cells in vitro and significantly impeded tumor progression in vivo without toxicity to normal tissues [143]. A recent study tested 10 cancer cell lines with AA and the results showed that pharmacologic ascorbic acid induced cytotoxicity in all tested cancer cells, with IC50 less than 4 mM, a concentration easily achievable in humans.…”

Section: Ascorbic Acid: Evidence Of Transla-tional Efficacy Against Cmentioning

confidence: 99%

Ascorbic Acid in Cancer Chemoprevention: Translational Perspectives and Efficacy

Ullah¹,

Bhat²,

Hussain³

et al. 2012

CDT

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Chemoprevention, which is referred to as the use of nontoxic natural or synthetic chemicals to intervene in multistage carcinogenesis has since decades attracted a considerable interest in plant-derived chemical constituents often termed as "phytochemicals" or sometimes as "Nutraceuticals" in case they are derived from dietary sources. A comprehensive search of the literature show that such an interest in natural product pharmacology has surged in the last 25 years and particularly risen at exponential rates since the last one decade. Phytochemicals such as curcumin (from spice turmeric), resveratrol (from red wine) and genistein (from soy) share the major efforts as indicated by overwhelming publications, despite skepticism concerning their bioavailability. Ascorbic acid (AA), the popular anti-oxidant in fruits and vegetables, has even a longer historical perspective than these dietary agents as for more than 35 years; there had been lingering questions about the efficacy of AA in cancer therapy. The footprints of AA from "scurvy" to "cancer" though complex seems to carry potential provided the puzzle could be set right. The use of AA in cancer treatment has been debated extensively as evident from the literature but surprisingly the complementing early phase bench work on the mechanistic studies for anticancer action was rather retarded. Proposed mechanisms of action for AA in the prevention and treatment of cancer includes antioxidant as well as pro-oxidant properties, stimulation of the immune system, altering carcinogen metabolism, enhancement of collagen synthesis necessary for tumor encapsulation and interference with cancer cell signaling. The observation that the intravenous administration of AA enhances its bioavailability to the extent of deriving pharmacological benefits against cancer has in recent years partially supported the clinical plausibility (efficacy) of AA towards realizing its translational advantage. Here, we provide an overview of AA with regard to its potential in the management of cancer disease.

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Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models

Cited by 47 publications

References 46 publications

Ascorbic Acid and a Cytostatic Inhibitor of Glycolysis Synergistically Induce Apoptosis in Non-Small Cell Lung Cancer Cells

Ascorbic Acid and a Cytostatic Inhibitor of Glycolysis Synergistically Induce Apoptosis in Non-Small Cell Lung Cancer Cells

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

Ascorbic Acid in Cancer Chemoprevention: Translational Perspectives and Efficacy

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