RESUMEN
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.