title: Induction of death of leukemia cells by TW-74, a novel derivative of chloro-naphthoquinone.
abstract: We have previously shown that a 2-chloro-1,4-naphthoquinone derivative (TW-92) induces cell death in leukemia cells. TW-92 exhibited relatively high selectivity towards primary Acute Myeloid Leukemia (AML) cells, as compared to normal mononuclear cells. In view of the selectivity of this family of naphthoquinones, novel chloroaminophenylnaphthoquinone isomers with different methyl substitutions on the phenyl ring were synthesized, and their effect on leukemia cells was tested. These compounds induced cell death in U937 human myeloid leukemia cells, which was prominent following 48 h of culture. Structure-activity relationship studies revealed that TW-74, a novel chloronaphthoquinone with a methyl group at the meta (m) position, was the most active derivative in inducing apoptosis. The mechanism underlying cell death induction by TW-74 was further investigated in U937 cells, a monocytic cell line which serves as a sensitive model of apoptosis induction. TW-74 induced rapid activation of Mitogen Activated Protein Kinases (MAPKs). It caused swelling of isolated rat liver mitochondria and an early reduction of mitochondrial membrane potential in intact cells, indicative of a direct effect on mitochondria. Apoptosis induced by TW-74 was accompanied by cytochrome C release and caspase activation. TW-74 induced down- regulation of (BCL2), an anti-apoptotic protein. Furthermore, TW-74 induced selective dose-dependent cell death in primary B-Chronic Lymphocytic Leukemia (CLL) cells. These findings demonstrate that chloronaphthoquiniones use common as well as diverse mechanisms for the induction of cell death. The data reported here warrant further studies of the utility of TW-74 in the treatment of CLL.
authors.affiliation: Department. of Clinical Biochemistry, Ben-Gurion University of the Negev, Beer-Sheva, 84101 Israel.
authors.forename: Maher
authors.initials: M
authors.lastname: Hallak
authors.forename: Basant K
authors.initials: BK
authors.lastname: Thakur
authors.forename: Thida
authors.initials: T
authors.lastname: Winn
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
authors.forename: Shmuel
authors.initials: S
authors.lastname: Bittner
authors.forename: Yosef
authors.initials: Y
authors.lastname: Granot
authors.forename: Itai
authors.initials: I
authors.lastname: Levy
authors.forename: Ilana
authors.initials: I
authors.lastname: Nathan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000138:chemical synthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D020298:U937 Cells / Q000187:drug effects
chemical_list: D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases