l-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide-mediated mechanisms

Park, Sung Yong; Han, Seong‐Su; Park, Chan H.; Hahm, Eun‐Ryeong; Lee, Sook J.; Park, Hye K.; Lee, Se‐Hoon; Kim, Won S.; Jung, Chul Won; Park, Keunchil; Riordan, Hugh D.; Kimler, Bruce F.; Kım, Kihyun; Lee, Je‐Ho

doi:10.1016/j.biocel.2004.04.005

Cited by 83 publications

(86 citation statements)

References 26 publications

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“…In vitro effects of ascorbate on death and survival of cell lines have been reported, but there are multiple experimental concerns. For example, reports compared an experimental condition to that with no ascorbate at all (43,44), but such a condition has had unclear physiologic relevance, because ascorbate outside and inside cells is always present unless there is severe scurvy. It was unclear whether observed effects were due to extracellular or intracellular ascorbate, or both (12,(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

“…For example, reports compared an experimental condition to that with no ascorbate at all (43,44), but such a condition has had unclear physiologic relevance, because ascorbate outside and inside cells is always present unless there is severe scurvy. It was unclear whether observed effects were due to extracellular or intracellular ascorbate, or both (12,(43)(44)(45)(46). Some experiments have used widely varying incubation times and ascorbate concentrations that have had no corresponding clinical context, making interpretation difficult.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues

Chen

Espey²,

Krishna³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

955

1,051

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Human pharmacokinetics data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentrations could have an unanticipated role in cancer treatment. Our goals here were to test whether ascorbate killed cancer cells selectively, and if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC 50 values of <4 mM, a concentration easily achievable i.v. Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC 50 of 0.5 mM) and suitability for addressing mechanisms. Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis͞necrosis. Cell death was independent of metal chelators and absolutely dependent on H 2O2 formation. Cell death from H2O2 added to cells was identical to that found when H2O2 was generated by ascorbate treatment. H2O2 generation was dependent on ascorbate concentration, incubation time, and the presence of 0.5-10% serum, and displayed a linear relationship with ascorbate radical formation. Although ascorbate addition to medium generated H 2O2, ascorbate addition to blood generated no detectable H 2O2 and only trace detectable ascorbate radical. Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H 2O2, and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H 2O2 may be beneficial.cell death ͉ ascorbate radical

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues

Chen

Espey²,

Krishna³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

955

1,051

View full text Add to dashboard Cite

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“…1). It has previously been reported that ascorbate induces cell death via PKCδ pathway in neuroblastoma cells (27), the Ca 2+ signal in human hepatoma cells (28), glioblastoma cells, renal carcinoma cells (29), and the caspase-dependent pathway in melanoma cells (30). Based on these studies, we examined the effect of some chemical inhibitors, such as rottlerin, a PKCδ specific inhibitor, nifedipine, a Ca 2+ signal blocker, a pancaspase inhibitor, and MG132, an AIF blocker (19), on ascorbate-induced cell death.…”

Section: Discussionmentioning

confidence: 99%

Ascorbate (vitamin C) induces cell death through the apoptosis-inducing factor in human breast cancer cells

et al. 2007

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Abstract. Although ascorbate (Vitamin C) has been shown to inhibit cell growth and induce cell death in variety of cancer cells, results reported in other studies are inconsistent with this conclusion. It was previously reported that ascorbate induces apoptosis in human breast cancer cells. However, the molecular mechanism for this is not clear. In this study, we demonstrate that ascorbate induces cell death through the apoptosis-inducing factor (AIF) in the human breast cancer cell lines, SK-BR3 and Hs578T, but not in a normal breast cell line, Hs578. Ascorbate treatment caused the nuclear translocation of AIF, which is retained in the mitochondria in healthy cells, but caspase cleavage is not induced. Moreover, MG132, an inhibitor of AIF release from mitochondria, blocked the induction of cell death. Furthermore, cells that had been treated with human AIF-specific siRNA resisted cell death induced by ascorbate, implying that the translocation of AIF from mitochondria to the nucleus is responsible for ascorbate-mediated cell death. Therefore, these results suggest that ascorbate activates a caspase-independent and AIFmediated cell death pathway in human breast cancer cells, SK-BR3, and Hs578T.

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“…The osteogenic effects reported for VOAsc were observed at doses of 2.5-25 mM, which are at least 6-60-fold lower than the ascorbic acid concentration used in the mineralization induction medium (145 mM). Recently, Park et al (2004) reported that ascorbic acid inhibited cell proliferation and induced apoptosis in leukemia cells via hydrogen peroxidemediated mechanisms. These effects were detected at concentrations of 0.25-1.0 mM, which are much higher doses than those used in our present study.…”

Section: Discussionmentioning

confidence: 99%

Osteogenic activity of vanadyl(IV)–ascorbate complex: Evaluation of its mechanism of action

Cortizo

Molinuevo

Barrio

et al. 2006

The International Journal of Biochemistry & Cell Biology

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We have previously shown that different vanadium(IV) complexes regulate osteoblastic growth. Since vanadium compounds are accumulated in vivo in bone, they may affect bone turnover. The development of vanadium complexes with different ligands could be an alternative strategy of use in skeletal tissue engineering. In this study, we have investigated the osteogenic properties of a vanadyl(IV)-ascorbate (VOAsc) complex, as well as its possible mechanisms of action, on two osteoblastic cell lines in culture. VOAsc (2.5-25 mM) significantly stimulated osteoblastic proliferation (113-125% basal, p < 0.01) in UMR106 cells, but not in the MC3T3E1 cell line. VOAsc (5-100 mM) dose-dependently stimulated type-I collagen production (107-156% basal) in osteoblasts. After 3 weeks of culture, 5-25 mM VOAsc increased the formation of nodules of mineralization in MC3T3E1 cells (7.7-20-fold control, p < 0.001). VOAsc (50-100 mM) significantly stimulated apoptosis in both cell lines (170-230% basal, p < 0.02-0.002), but did not affect reactive oxygen species production. The complex inhibited alkaline and neutral phosphatases from osteoblastic extracts with semi-maximal effect at 10 mM doses. VOAsc induced the activation and redistribution of P-ERK in a time-and dose-dependent manner. Inhibitors of the mitogen activated protein kinases (MAPK) pathway (PD98059 and UO126) partially blocked the VOAsc-enhanced osteoblastic proliferation and collagen production. In addition, wortmanin, a PI-3-K inhibitor and type-L channel blocker nifedipine also partially abrogated these effects of VOAsc on osteoblasts. Our in vitro results suggest that this vanadyl(IV)-ascorbate complex could be a useful pharmacological tool for bone tissue regeneration. © 2005 Elsevier Ltd. All rights reserved.

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l-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide-mediated mechanisms

Cited by 83 publications

References 26 publications

Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues

Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues

Ascorbate (vitamin C) induces cell death through the apoptosis-inducing factor in human breast cancer cells

Osteogenic activity of vanadyl(IV)–ascorbate complex: Evaluation of its mechanism of action

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