Hydroxycoumarins as apoptosis inducers in human leukemic cells. Part II Study of the mechanism of action of 7,8-dihydroxy-4-methylcoumarin

RIVEIRO M.E; VAZQUEZ R; MOGLIONI A; GOMEZ N; BALDI A; DAVIO C; SHAYO C

BIOCHEMICAL PHARMACOLOGY

Elsevier Science Inc

Año: 2008 p. 725 - 736

0006-2952

The search for new drugs requires the deep understanding of the molecular basis of drug action, being necessary the elucidation of the mechanism of action together with the understanding of the relationship between structure and activity. In the accompanying paper, we report a structure-activity relationship study showing that certain structural requirements are required for hydroxycoumarins to induce apoptosis in human U-937 leukemic cells [Riveiro, et al. In this issue]. In the present study, we evaluated the pro-apoptotic activity of 7,8-dihydroxy-4-methylcoumarin (DHMC) and its underlying mechanisms in both human leukemic cells and peripheral blood mononuclear cells. Here, we present evidence that DHMC induced selective and concentration-dependent apoptosis in human leukemia cells. The pro-apoptotic effect of DHMC was mediated by activation of p-JNKs and inhibition of the ERK1/2 and PI3K/Akt pathways, with no participation of the p38 cascade after 24 h of treatment. Indeed, downregulation of the proto-oncogene c-myc as well as induction of the cell cycle inhibitor p21WAF1/CIP1 through a p53 independent mechanism were observed in U-937 cells. These findings further suggest that DHCM may have a potential therapeutic role in the future treatment of hematological malignancies.