Biochemical mechanism underlying the pro-apoptotic activity of 7,8-dihydroxy-4 methylcoumarin in human leukemic cells

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

BIOCHEMICAL PHARMACOLOGY

Elsevier

Año: 2008 vol. 3 p. 725 - 736

0006-2952

The search for new drugs requires a deep understanding of the molecular basis of drugaction, being necessary the elucidation of the mechanism of action with the understandingof the relationship between structure and activity. In the present study, we evaluated thepro-apoptotic activity of 7,8-dihydroxy-4-methylcoumarin (DHMC) and its underlyingmechanisms in human leukemic cells. Here, we present evidence that DHMC inducedselective and concentration-dependent apoptosis in human leukemic cells. The pro-apoptoticeffect of DHMC was mediated by activation of the JNKs and inhibition of the ERK1/2 andPI3K/Akt pathways, with no participation of the p38 cascade after 24 h of treatment. Indeed,down-regulation of the proto-oncogene c-myc as well as induction of the cell cycle inhibitorp21WAF1/CIP1 through a p53 independent mechanism were observed in U-937 cells. Thesefindings suggest that DHCM may have a potential therapeutic role in the future treatment ofhematological malignancies.