Cell differentiation and apoptosis of monocytic and promyelocytic leukemia cells (U-937 and HL-60) by tryptanthrin, an active ingredient of Polygonum tinctorium Lour.
Tryptanthrin, a bioactive ingredient of Polygonum tinctorium Lour., is a member of the Indigo plant family and has potent cytocidal effects on various human leukemia cells in vitro. At low concentrations, tryptanthrin enhanced the expression of cell differentiation (CD) markers in human monocytic (U-937) and promyelocytic (HL-60) leukemia cells indicative of differentiation to monocytes/macrophages. Furthermore, nitroblue tetrazolium (NBT) reductive and alpha-naphthyl butyrate esterase (NBE) activities were markedly increased after treatment. Tryptanthrin was more potent than dimethyl sulfoxide (DMSO) at inducing U-937 cell differentiation into monocytes/macrophages. After treatment with higher concentrations of tryptanthrin for 24 h, cytoplasmic vacuolation and destruction of mitochondria were observed. The leukemia cells died via apoptosis 48 h after treatment. Cytoplasmic vacuolation and apoptotic changes correlated with the dysfunction of mitochondria. Electron microscopic observations revealed marked swelling and destruction of mitochondria after exposure of the leukemia cells to tryptanthrin. Exposure to tryptanthrin enhanced Fas-induced apoptosis and increased caspase-3 activity before induction of apoptosis. These results show that low concentrations of tryptanthrin can induce differentiation of leukemia cells but higher concentrations will kill leukemia cells through apoptosis, possibly through a caspase-3/Fas antigen pathway.
Kimoto
T
T
Hayashibara Biochemical Laboratories Inc., Fujisaki Institute, Okayama, Japan.
Hino
K
K
Koya-Miyata
S
S
Yamamoto
Y
Y
Takeuchi
M
M
Nishizaki
Y
Y
Micallef
M J
MJ
Ushio
S
S
Iwaki
K
K
Ikeda
M
M
Kurimoto
M
M
D015703:Antigens, CD / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000648:ultrastructure; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004950:Esterases / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009580:Nitroblue Tetrazolium / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D020298:U937 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000378:metabolism
D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D011799:Quinazolines; D019014:fas Receptor; C046243:tryptanthrine; D009580:Nitroblue Tetrazolium; D004950:Esterases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases