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

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

doi:10.1016/j.biocel.2004.04.005

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

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

Department of Pediatrics

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

L-Ascorbic acid (LAA) is being investigated clinically for the treatment of patients with acute myeloid leukemia (AML) based on the observed effects of LAA on AML progenitor cells in vitro. However, the mechanism for LAA-induced cytoreduction remains to be elucidated. LAA at concentrations of 0.25-1.0 mM induced a dose- and time-dependent inhibition of proliferation in three AML cell lines and also in leukemic cells from peripheral blood specimens obtained from three patients with AML. In contrast, ovarian cancer cell lines were only minimally affected. Flow cytometric analysis showed that LAA at concentrations of 0.25-1.0 mM could significantly induce apoptosis in the AML cell lines. LAA induced oxidation of glutathione to oxidized form (GSSG) and subsequent H ₂O ₂ accumulation in a concentration-dependent manner, in parallel to induction of apoptosis. The direct role of H ₂O ₂ in the induction of apoptosis in AML cells was clearly demonstrated by the finding that catalase could completely abrogate LAA-induced apoptosis. Induction of apoptosis in LAA-treated AML cells involved a dose-dependent increase of Bax protein, release of cytochrome C from mitochondria to cytosol, activation of caspase 9 and caspase 3, and cleavage of poly[ADP-ribose] polymerase. In conclusion, LAA can induce apoptosis in AML cells, and this is clearly due to H ₂O ₂ which accumulates intracellularly as a result of oxidation of reduced glutathione by LAA.

Original language	English (US)
Pages (from-to)	2180-2195
Number of pages	16
Journal	International Journal of Biochemistry and Cell Biology
Volume	36
Issue number	11
DOIs	https://doi.org/10.1016/j.biocel.2004.04.005
State	Published - Nov 2004

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Biochemistry
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.biocel.2004.04.005

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Park, S., Han, S. S., Park, C. H., Hahm, E. R., Lee, S. J., Park, H. K., Lee, S. H., Kim, W. S., Jung, C. W., Park, K., Riordan, H. D., Kimler, B. F., Kim, K., & Lee, J. H. (2004). L-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide-mediated mechanisms. International Journal of Biochemistry and Cell Biology, 36(11), 2180-2195. https://doi.org/10.1016/j.biocel.2004.04.005

@article{83cfae406748444aaab9852f2c1e4b13,

title = "L-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide-mediated mechanisms",

abstract = "L-Ascorbic acid (LAA) is being investigated clinically for the treatment of patients with acute myeloid leukemia (AML) based on the observed effects of LAA on AML progenitor cells in vitro. However, the mechanism for LAA-induced cytoreduction remains to be elucidated. LAA at concentrations of 0.25-1.0 mM induced a dose- and time-dependent inhibition of proliferation in three AML cell lines and also in leukemic cells from peripheral blood specimens obtained from three patients with AML. In contrast, ovarian cancer cell lines were only minimally affected. Flow cytometric analysis showed that LAA at concentrations of 0.25-1.0 mM could significantly induce apoptosis in the AML cell lines. LAA induced oxidation of glutathione to oxidized form (GSSG) and subsequent H 2O 2 accumulation in a concentration-dependent manner, in parallel to induction of apoptosis. The direct role of H 2O 2 in the induction of apoptosis in AML cells was clearly demonstrated by the finding that catalase could completely abrogate LAA-induced apoptosis. Induction of apoptosis in LAA-treated AML cells involved a dose-dependent increase of Bax protein, release of cytochrome C from mitochondria to cytosol, activation of caspase 9 and caspase 3, and cleavage of poly[ADP-ribose] polymerase. In conclusion, LAA can induce apoptosis in AML cells, and this is clearly due to H 2O 2 which accumulates intracellularly as a result of oxidation of reduced glutathione by LAA.",

author = "Seyeon Park and Han, {Seong Su} and Park, {Chan H.} and Hahm, {Eun Ryeong} and Lee, {Sook J.} and Park, {Hye K.} and Lee, {Se Hoon} and Kim, {Won S.} and Jung, {Chul Won} and Keunchil Park and Riordan, {Hugh D.} and Kimler, {Bruce F.} and Kihyun Kim and Lee, {Je Ho}",

note = "Funding Information: This research was supported by a grant from Jin Yang Pharmaceutical Co. Ltd. ",

year = "2004",

month = nov,

doi = "10.1016/j.biocel.2004.04.005",

language = "English (US)",

volume = "36",

pages = "2180--2195",

journal = "International Journal of Biochemistry",

issn = "1357-2725",

publisher = "Elsevier Limited",

number = "11",

}

Park, S, Han, SS, Park, CH, Hahm, ER, Lee, SJ, Park, HK, Lee, SH, Kim, WS, Jung, CW, Park, K, Riordan, HD, Kimler, BF, Kim, K & Lee, JH 2004, 'L-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide-mediated mechanisms', International Journal of Biochemistry and Cell Biology, vol. 36, no. 11, pp. 2180-2195. https://doi.org/10.1016/j.biocel.2004.04.005

TY - JOUR

T1 - L-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide-mediated mechanisms

AU - Park, Seyeon

AU - Han, Seong Su

AU - Park, Chan H.

AU - Hahm, Eun Ryeong

AU - Lee, Sook J.

AU - Park, Hye K.

AU - Lee, Se Hoon

AU - Kim, Won S.

AU - Jung, Chul Won

AU - Park, Keunchil

AU - Riordan, Hugh D.

AU - Kimler, Bruce F.

AU - Kim, Kihyun

AU - Lee, Je Ho

N1 - Funding Information: This research was supported by a grant from Jin Yang Pharmaceutical Co. Ltd.

PY - 2004/11

Y1 - 2004/11

N2 - L-Ascorbic acid (LAA) is being investigated clinically for the treatment of patients with acute myeloid leukemia (AML) based on the observed effects of LAA on AML progenitor cells in vitro. However, the mechanism for LAA-induced cytoreduction remains to be elucidated. LAA at concentrations of 0.25-1.0 mM induced a dose- and time-dependent inhibition of proliferation in three AML cell lines and also in leukemic cells from peripheral blood specimens obtained from three patients with AML. In contrast, ovarian cancer cell lines were only minimally affected. Flow cytometric analysis showed that LAA at concentrations of 0.25-1.0 mM could significantly induce apoptosis in the AML cell lines. LAA induced oxidation of glutathione to oxidized form (GSSG) and subsequent H 2O 2 accumulation in a concentration-dependent manner, in parallel to induction of apoptosis. The direct role of H 2O 2 in the induction of apoptosis in AML cells was clearly demonstrated by the finding that catalase could completely abrogate LAA-induced apoptosis. Induction of apoptosis in LAA-treated AML cells involved a dose-dependent increase of Bax protein, release of cytochrome C from mitochondria to cytosol, activation of caspase 9 and caspase 3, and cleavage of poly[ADP-ribose] polymerase. In conclusion, LAA can induce apoptosis in AML cells, and this is clearly due to H 2O 2 which accumulates intracellularly as a result of oxidation of reduced glutathione by LAA.

AB - L-Ascorbic acid (LAA) is being investigated clinically for the treatment of patients with acute myeloid leukemia (AML) based on the observed effects of LAA on AML progenitor cells in vitro. However, the mechanism for LAA-induced cytoreduction remains to be elucidated. LAA at concentrations of 0.25-1.0 mM induced a dose- and time-dependent inhibition of proliferation in three AML cell lines and also in leukemic cells from peripheral blood specimens obtained from three patients with AML. In contrast, ovarian cancer cell lines were only minimally affected. Flow cytometric analysis showed that LAA at concentrations of 0.25-1.0 mM could significantly induce apoptosis in the AML cell lines. LAA induced oxidation of glutathione to oxidized form (GSSG) and subsequent H 2O 2 accumulation in a concentration-dependent manner, in parallel to induction of apoptosis. The direct role of H 2O 2 in the induction of apoptosis in AML cells was clearly demonstrated by the finding that catalase could completely abrogate LAA-induced apoptosis. Induction of apoptosis in LAA-treated AML cells involved a dose-dependent increase of Bax protein, release of cytochrome C from mitochondria to cytosol, activation of caspase 9 and caspase 3, and cleavage of poly[ADP-ribose] polymerase. In conclusion, LAA can induce apoptosis in AML cells, and this is clearly due to H 2O 2 which accumulates intracellularly as a result of oxidation of reduced glutathione by LAA.

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DO - 10.1016/j.biocel.2004.04.005

M3 - Article

C2 - 15313465

AN - SCOPUS:4143085009

SN - 1357-2725

VL - 36

SP - 2180

EP - 2195

JO - International Journal of Biochemistry

JF - International Journal of Biochemistry

IS - 11

ER -

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

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