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The signaling pathways for compound DC072 induced apoptosis in acute myeloid leukemia
Author(s) -
Li Kathy keqin,
Chen Limin,
Lu Juyan,
Luo Liufei,
Luo Cheng
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb104
Subject(s) - myeloid leukemia , sphingosine kinase , mcl1 , sphingosine , apoptosis , cancer research , leukemia , sphingolipid , ceramide , protein kinase b , sphingosine 1 phosphate , chemistry , signal transduction , biology , microbiology and biotechnology , biochemistry , gene , downregulation and upregulation , immunology , receptor
Sphingosine‐1‐phosphate (S1P) signaling are attractive targets for development of new therapeutics for cancers. By using computer‐aided drug design, we found a series of chemical analogues for Sphingosine or S1P, and then we tested their biological activities in enzymatic and cellular level. One of the analogues named DC072 shows very good anti‐cancer biological effects in some leukemia cells. DC072 could dramatically induce apoptosis of acute myeloid leukemia (AML) cell line kasumi‐1, and markedly reduce the growth of AML xenograft tumors in nude mice. We studied the genome‐wide gene expression profile by microarray analysis. There are group genes are associated with lipid metabolism. We further explored the molecular networking of how DC072 induced AML cell apoptosis. It was demonstrated that DC072 inhibited the activity of sphingosine kinase 1 (SPHK1) to make ceramide accumulation within the AML cells, and ceramide down regulated nutrition channel proteins and activated PP2A. PP2A activation triggered phosphorylations of c‐kit and Akt proteins, and ultimately resulted in the changes of downstream apoptotic cascade proteins such as Bcl‐2, Bcl‐XL, caspase 3 and PARP. Our data suggested that DC072 could be a potential addition to the therapeutic armamentarium in leukemia.