title: Cytotoxic effects of novel phytosphingosine derivatives, including N,N-dimethylphytosphingosine and N-monomethylphytosphingosine, in human leukemia cell line HL60.
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.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sook Ryun
authors.initials: SR
authors.lastname: Park
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Cho
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Moon
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kong
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
authors.forename: Seonyang
authors.initials: S
authors.lastname: Park
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; C542681:N,N-dimethylphytosphingosine; C548294:N-monomethylphytosphingosine; C012491:phytosphingosine; D013110:Sphingosine