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Cytotoxic effects of novel phytosphingosine derivatives, including N,N-dimethylphytosphingosine and N-monomethylphytosphingosine, in human leukemia cell line HL60

Cited 12 time in Web of Science Cited 12 time in Scopus
Authors
Park, Sook Ryun; Cho, Hyo Jin; Moon, Kyung Jin; Chun, Kyung-Hee; Yoon, Sung-Soo; Park, Seonyang; Lee, Jong Seok; Kong, Sun-Young
Issue Date
2010-01
Publisher
TAYLOR & FRANCIS LTD
Citation
LEUKEMIA & LYMPHOMA; Vol.51 1; 132-145
Keywords
N-monomethylphytosphingosineN,N-dimethylphytosphingosineleukemiadaunorubicincytotoxicityapoptosis
Abstract
Novel phytosphingosine derivatives have been developed based on the inhibition of sphingosine kinase, which has been implicated in cell growth and inhibition of ceramide-mediated apoptosis. This study evaluated the cytotoxic effects and underlying mechanisms of action of novel phytosphingosine derivatives, including N-monomethylphytosphingosine (MMPH) and N,N-dimethylphytosphingosine (DMPH) and the pegylated forms MMPH-PEG and DMPH-PEG, in human leukemia HL60 cells. In viability and proliferation assays using WST-1, all four drugs induced suppression of cell growth and viability in a concentration-dependent manner. Among them, DMPH had the highest antileukemic activity and induced apoptosis via caspase-8, caspase-3, and caspase-9 activation. The apoptotic effect was also associated with Fas/FasL upregulation, Bid cleavage, Bcl-2 downregulation, Bax upregulation, mitochondrial membrane depolarization, and cytochrome c release. DMPH decreased the phosphorylation of ERK and inhibited daunorubicin-induced ERK activation. Furthermore, DMPH displayed synergistic cytotoxicity with daunorubicin in a sequence-dependent manner. Our findings indicate that DMPH has potential as an effective cytotoxic agent for leukemia.
ISSN
1042-8194
Language
English
URI
http://hdl.handle.net/10371/76554
DOI
https://doi.org/10.3109/10428190903383419
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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