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Eur J Pharmacol. 2010 Dec 1;648(1-3):31-8. doi: 10.1016/j.ejphar.2010.08.020. Epub 2010 Sep 16.

3,6-Dihydroxyflavone induces apoptosis in leukemia HL-60 cell via reactive oxygen species-mediated p38 MAPK/JNK pathway.

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1
Research Center for Nutrition and Food Safety, Third Military University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing, 400038 China.

Abstract

We have previously selected a promising anti-cancer agent 3,6-dihydroxyflavone by pharmacodynamic experiments. In the present study, we investigated its pro-apoptosis mechanisms in leukemia HL-60 cell. Our data revealed that 3,6-dihydroxyflavone dose- and time-dependently decreases cell viability and induces apoptosis by activating caspase cascade, cleaving poly (ADP-ribose) polymerase (PARP). The anti-cancer effects of 3,6-dihydroxyflavone are associated with the generation of reactive oxygen species, the altered glutathione-redox balance as significantly decreased glutathione (GSH) and its ratio to gluthatione disulfide (GSSG), and the accumulation of lipid peroxidation indicator malondialdehyde. Addition of antioxidant N-acetylcysteine (NAC) prevents the elevation of reactive oxygen species induced by 3,6-dihydroxyflavone and partially suppresses the cytotoxic effects. Furthermore, 3,6-dihydroxyflavone reduces cell membrane fluidity and induces the loss of mitochondrial membrane potential. 3,6-Dihydroxyflavone was also found to modulate the activities of mitogen-activated protein kinase (MAPK) family members, which includes increased protein kinase of 38 kDa (p38), c-Jun N-terminal kinase (JNK), and decreased extracellular signal-regulated kinase (ERK) activation. The effect of 3,6-dihydroxyflavone on MAPKs pathway could be abrogated by co-treatment with NAC. Taking together, our data suggested that 3,6-dihydroxyflavone increases intracellular oxidative stress and lipid peroxidation, thereby affecting the physical and functional properties of plasma membrane, as well as MAPKs signal pathway, which are likely to play a role in the 3,6-dihydroxyflavone-induced HL-60 cell cytotoxicities.

PMID:
20840847
DOI:
10.1016/j.ejphar.2010.08.020
[Indexed for MEDLINE]

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