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.
|
Authors | Sook Ryun Park, Hyo Jin Cho, Kyung Jin Moon, Kyung-Hee Chun, Sun-Young Kong, Sung-Soo Yoon, Jong Seok Lee, Seonyang Park |
Journal | Leukemia & lymphoma
(Leuk Lymphoma)
Vol. 51
Issue 1
Pg. 132-45
(Jan 2010)
ISSN: 1029-2403 [Electronic] United States |
PMID | 20001229
(Publication Type: Journal Article)
|
Chemical References |
- Antineoplastic Agents
- Caspase Inhibitors
- N,N-dimethylphytosphingosine
- N-monomethylphytosphingosine
- phytosphingosine
- Sphingosine
|
Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
- Caspase Inhibitors
- Cell Cycle
- Cell Line, Tumor
- Cell Survival
- Chemistry, Pharmaceutical
(methods)
- Drug Design
- Drug Screening Assays, Antitumor
(methods)
- Gene Expression Regulation, Leukemic
- HL-60 Cells
- Humans
- Leukemia
(drug therapy)
- Sphingosine
(analogs & derivatives, pharmacology)
|