Induction of apoptosis in human myeloid leukemic cells by 1'-acetoxychavicol acetate through a mitochondrial- and Fas-mediated dual mechanism.
OBJECTIVE
The purpose of this investigation was to determine the antileukemic effects of 1'-acetoxychavicol acetate (ACA) obtained from rhizomes of the commonly used ethno-medicinal plant Languas galanga (Zingiberaceae).


METHODS
We evaluated the effects of ACA on various myeloid leukemic cells in vitro and in vivo. We further examined the molecular mechanisms of ACA-induced apoptosis in myeloid leukemic cells.


RESULTS
Low-dose ACA dramatically inhibited cellular growth of leukemic cells by inducing apoptosis. Because NB4 promyelocytic leukemic cells were most sensitive to ACA, we used NB4 cells for further analyses. Production of reactive oxygen species triggered ACA-induced apoptosis. ACA-induced apoptosis in NB4 cells was in association with the loss of mitochondrial transmembrane potential (DeltaPsim) and activation of caspase-9, suggesting that ACA-induced death signaling is mediated through a mitochondrial oxygen stress pathway. In addition, ACA activated Fas-mediated apoptosis by inducing of casapse-8 activity. Pretreatment with the thiol antioxidant N-acetyl-L-cysteine (NAC) did not inhibit caspase-8 activation, and the antagonistic anti-Fas antibody ZB4 did not block generation of reactive oxygen species, indicating that both pathways were involved independently in ACA-induced apoptosis. Furthermore, ACA had a survival advantage in vivo in a nonobese diabetic/severe combined immunodeficient mice leukemia model without any toxic effects.


CONCLUSIONS
We conclude that ACA induces apoptosis in myeloid leukemic cells via independent dual pathways. In addition, ACA has potential as a novel therapeutic agent for the treatment of myeloid leukemia.
Ito
Keisuke
K
Departments of Internal Medicine and Pathology, Keio University School of Medicine, Tokyo, Japan.
Nakazato
Tomonori
T
Murakami
Akira
A
Yamato
Kenji
K
Miyakawa
Yoshitaka
Y
Yamada
Taketo
T
Hozumi
Nobumichi
N
Ohigashi
Hajime
H
Ikeda
Yasuo
Y
Kizaki
Masahiro
M
D000328:Adult; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001592:Benzyl Alcohols; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D008517:Phytotherapy; D013729:Terpenes / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000187:drug effects / Q000502:physiology*
D000970:Antineoplastic Agents; D001592:Benzyl Alcohols; D013729:Terpenes; D019014:fas Receptor; D020169:Caspases; C047948:1'-acetoxychavicol acetate