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Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease.

Publication ,  Journal Article
Lee, WR; Shen, SC; Lin, HY; Hou, WC; Yang, LL; Chen, YC
Published in: Biochem Pharmacol
January 15, 2002

Seven structurally related flavonoids including luteolin, nobiletin, wogonin, baicalein, apigenin, myricetin and fisetin were used to study their biological activities on the human leukemia cell line, HL-60. On MTT assay, wogonin, baicalein, apigenin, myricetin and fisetin showed obvious cytotoxic effects on HL-60 cells, with wogonin and fisetin being the most-potent apoptotic inducers among them. The cytotoxic effects of wogonin and fisetin were accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including DNA fragmentation, apoptotic bodies and the sub-G1 ratio. Treatment with an apoptosis-inducing concentration of wogonin or fisetin causes rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity. Further, cleavage of poly(ADP-ribose) polymerase (PARP) and decrease of pro-caspase 3 protein were detected in wogonin- and fisetin-treated HL-60 cells. An increase in the pro-apoptotic protein, bax, and a decrease in the anti-apoptotic protein, Mcl-1, were detected in fisetin- and wogonin-treated HL-60 cells. However, Bcl-2, Bcl-XL, and Bad all remained unchanged in wogonin- and fisetin-treated HL-60 cells. In vitro chromatin digestion revealed that endonuclease activity was profoundly enhanced in wogonin- and fisetin-treated HL-60 cells, and the addition of ethylenediaminetetraacetic acid (EDTA) or ethyleneglycoltetraacetic acid (EGTA) into the reaction blocked endonuclease activation and at an optimum pH of 7.5. The caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor, Ac-YVAD-CHO, attenuated wogonin- and fisetin-induced DNA ladders, PARP cleavage, and endonuclease activation. Pretreatment of HL-60 cells with N-acetyl-cysteine or catalase efficiently inhibited H(2)O(2) (200 microM)-induced apoptosis, but showed no inhibitory effect on wogonin- and fisetin-induced DNA ladders, caspase 3 activation, or bax protein induction. Decrease in endogenous ROS production was detected in wogonin- and fisetin-treated HL-60 cells by DCHF-DA assay. In conclusion, our experiments indicate that a decrease in intracellular peroxide level was involved in wogonin- and fisetin-induced apoptosis; activation of caspase 3 and endonuclease, induction of bax protein and suppression of Mcl-1 protein were detected in the process.

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Published In

Biochem Pharmacol

DOI

ISSN

0006-2952

Publication Date

January 15, 2002

Volume

63

Issue

2

Start / End Page

225 / 236

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-bcl-2
  • Poly(ADP-ribose) Polymerases
  • Pharmacology & Pharmacy
  • Oligopeptides
  • Leukemia, Promyelocytic, Acute
  • Hydrogen Peroxide
  • Humans
  • HL-60 Cells
 

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Lee, W. R., Shen, S. C., Lin, H. Y., Hou, W. C., Yang, L. L., & Chen, Y. C. (2002). Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease. Biochem Pharmacol, 63(2), 225–236. https://doi.org/10.1016/s0006-2952(01)00876-0
Lee, Woan Rouh, Shing Chuan Shen, Hui Yi Lin, Wen Chi Hou, Ling Ling Yang, and Yen Chou Chen. “Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease.Biochem Pharmacol 63, no. 2 (January 15, 2002): 225–36. https://doi.org/10.1016/s0006-2952(01)00876-0.
Lee, Woan Rouh, et al. “Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease.Biochem Pharmacol, vol. 63, no. 2, Jan. 2002, pp. 225–36. Pubmed, doi:10.1016/s0006-2952(01)00876-0.
Journal cover image

Published In

Biochem Pharmacol

DOI

ISSN

0006-2952

Publication Date

January 15, 2002

Volume

63

Issue

2

Start / End Page

225 / 236

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-bcl-2
  • Poly(ADP-ribose) Polymerases
  • Pharmacology & Pharmacy
  • Oligopeptides
  • Leukemia, Promyelocytic, Acute
  • Hydrogen Peroxide
  • Humans
  • HL-60 Cells