3,6-Dihydroxyflavone induces apoptosis in leukemia HL-60 cell via reactive oxygen species-mediated p38 MAPK/JNK pathway.
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.
Chang
Hui
H
Research Center for Nutrition and Food Safety, Third Military University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing, 400038 China.
Lin
Hui
H
Yi
Long
L
Zhu
Jundong
J
Zhou
Yong
Y
Mi
Mantian
M
Zhang
Qianyong
Q
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007938:Leukemia / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008560:Membrane Fluidity / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C555160:3,6-dihydroxyflavone; D005419:Flavonoids; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D005978:Glutathione