"STRATEGIES FOR THE DEVELOPMENT OF NEW DRUGS"

DAVIO CARLOS

FFyB, UBA

Workshop; Internacional Workshop "STRATEGIES FOR THE DEVELOPMENT OF NEW DRUGS.; 2008

Organizador y responsable Dr. Carlos Davio. En el marco del Programa de Cooperación Científico-Tecnológica entre el Ministerio de Ciencia,

Beyond the mechanism of action of pro-apoptotic hydroxycoumarins in leukemic cells. Dr. Carlos Alberto Davio – Cátedra de Quimica Medicinal, FFyB, UBA. cardavio@ffyb.uba.ar   Driven by chemistry but increasingly guided by pharmacology and the clinical sciences, drug research has contributed more to the progress of medicine during the past century than any other scientific factor. The dramatic increase in the complexity of drug research is enforcing changes in the institutional basis of this interdisciplinary endeavor. Genome sciences, combined with bioinformatic tools, allow us to dissect the genetic basis of multifactorial diseases and to determine the most suitable points of attack for future medicines, thereby increasing the number of treatment options and having a deep impact on drug discovery. Nowadays, the search for new drugs requires a deep understanding of the molecular basis of drug action, being necessary the elucidation of the mechanism of action with the understanding of the relationship between structure and activity. In the present study, we evaluated the pro-apoptotic activity of 7,8-dihydroxy-4-methylcoumarin (DHMC) and its underlying mechanisms in human leukemic cells. DHMC displayed anti-proliferative effects inducing programmed cell death in different human leukemia cell lines such U-937 and HL-60. In this sense, we observed that DHMC exhibits lower toxicity in normal cells than in malignant cells. Besides, we described that DHMC-treated U-937 cells showed activation of the JNKs pathway at 18 h and down-regulation of p-ERK1/2 after 6 h but no detectable changes in phosphorylated p38. Furthermore, western blot analysis showed that Akt was highly expressed and phosphorylated in control cells, whereas in DHMC-treated cells Akt was inactivated at least within 18 h. On the other hand, the protooncogen c-Myc decreased after 3 h when U-937 cells underwent apoptosis induced by DHMC treatment  and the expression  of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 increased after 18 h U-937 cells exposure to 250 µM DHMC. So, the integration of the prosurvival and pro-apoptotic signaling pathways determines the final outcome in DHMC-treated U-937 cells triggering tumor-selective cell death.