Cytotoxic effects of novel phytosphingosine derivatives, including N,N-dimethylphytosphingosine and N-monomethylphytosphingosine, in human leukemia cell line HL60.
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.
Park
Sook Ryun
SR
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Cho
Hyo Jin
HJ
Moon
Kyung Jin
KJ
Chun
Kyung-Hee
KH
Kong
Sun-Young
SY
Yoon
Sung-Soo
SS
Lee
Jong Seok
JS
Park
Seonyang
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D061945:Caspase Inhibitors; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; C542681:N,N-dimethylphytosphingosine; C548294:N-monomethylphytosphingosine; C012491:phytosphingosine; D013110:Sphingosine