Induction of apoptosis in colorectal carcinoma cells treated with 4-hydroxy-2-nonenal and structurally related aldehydic products of lipid peroxidation.
The oxidation of polyunsaturated fatty acids during oxidative stress gives rise to a series of toxic alpha,beta-unsaturated aldehydes, including the electrophile 4-hydroxy-2-nonenal (4-HNE) and the related aldehydes, 4-hydroperoxy-2-nonenal (4-HPNE) and 4-oxo-2-nonenal (4-ONE). We synthesized these compounds, as well as the resolved enantiomers of 4-HNE, and compared their toxicities and apoptotic responses in the human colorectal cancer cell line RKO. All of these molecules execute similar death responses at comparable doses over almost identical time frames in RKO cells. The apoptotic response induced by 4-HPNE, 4-ONE, and 4-HNE enantiomers involves activation of caspases, proteolysis of downstream caspase targets, and nucleosomal DNA fragmentation. The results presented herein suggest that these molecules commonly activate certain signaling pathways that control cell death irrespective of their reactive properties.
West
James D
JD
Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37232-0146, USA.
Ji
Chuan
C
Duncan
Stephen T
ST
Amarnath
Venkataraman
V
Schneider
Claus
C
Rizzo
Carmelo J
CJ
Brash
Alan R
AR
Marnett
Lawrence J
LJ
D000447:Aldehydes / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000473:pathology*; D004249:DNA Damage; D006801:Humans; D015227:Lipid Peroxidation; D011506:Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000447:Aldehydes; D011506:Proteins; C027576:4-hydroxy-2-nonenal