Induction of apoptosis in a human leukemic cell line via reactive oxygen species modulation by antioxidants.
In the human acute myeloid leukemia cell line M07e, the growth factor interleukin-3 (IL-3) induces ROS formation, positively affecting Glut1-mediated glucose uptake and cell survival. The effect of IL-3 and exogenous hydrogen peroxide on cell viability seems to be mediated through inhibition of the cell death commitment, as shown by apoptotic markers such as caspase activities, apoptotic nuclei, and changes in the amount of proteins belonging to the Bcl-2 family. The pivotal role of ROS is confirmed using various antioxidants, such as EUK-134, ebselen, TEMPO, and hydroxylamine probe. In fact, these antioxidants, acting through different mechanisms, decrease glucose transport activity and cell proliferation activated by IL-3 or by low concentrations of hydrogen peroxide. Moreover, antioxidants foster programmed cell death commitment, as shown by the cited apoptotic parameters. EUK-134, a combined superoxide dismutase/catalase mimetic, opposes the effects of IL-3 and H(2)O(2), decreasing phosphorylation levels of signaling enzymes such as Akt, Src tyrosine kinase, and ERK. Results show that ROS production induced by IL-3 can protect leukemic cells from apoptosis, the effect being counteracted by antioxidants. This mechanism may play an important role in supporting acute myeloid leukemia treatment, thus representing a novel therapeutic strategy.
Maraldi
Tullia
T
Department of Biochemistry G. Moruzzi, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
Prata
Cecilia
C
Fiorentini
Diana
D
Zambonin
Laura
L
Landi
Laura
L
Hakim
Gabriele
G
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly; D003114:Colony-Forming Units Assay; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors; D007377:Interleukin-3 / Q000037:antagonists & inhibitors; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009942:Organometallic Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D012459:Salicylates / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D014162:Transfection; D019076:Transgenes / Q000235:genetics
D000975:Antioxidants; C433928:EUK-134; D051272:Glucose Transporter Type 1; D007377:Interleukin-3; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C495677:SLC2A1 protein, human; D012459:Salicylates; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D020169:Caspases