4,4´-DIMETHOXYBENZOPHENONE THIOSEMICARBAZONE: A NOVEL COMPOUND WITH SELECTIVE PROAPOPTOTIC ACTIVITY IN HUMAN LEUKEMIC CELLS. MOLECULAR MECHANISM OF ACTION.

CABRERA M; GOMEZ N; REMES LENICOV F; ECHEVERRIA E; SHAYO C; MOGLIONI A; FERNANDEZ N; DAVIO C

Congreso; Third south american symposium in dignal transduction and molecular medicine; 2015

Anti-mitotic therapies have been considered a hallmarkof strategies against abnormal proliferative cells. Focusing on the extensivelystudied family of thiosemicarbazone (TSC) compounds, we havepreviously identified the 4,4?-dimethoxybenzophenone thiosemicarbazone (T44Bf)as a promising pharmacological compound in a panel of human leukemia cell lines(HL60, U937, KG1a and Jurkat). Present findings indicate that T44Bf-mediated antiproliferative effectsare associated with a reversible chronic mitotic arrest caused by defectsin chromosome alignment, followed byprogrammed cell death induction. Furthermore, T44Bf selectively inducesapoptosis in leukemia cell lines when compared to normal peripheral bloodmononuclear cells. The underlying mechanism of action involves the activationof the mitochondria signaling pathway, with loss of mitochondrial membranepotential and sustained phosphorylation of anti-apoptotic proteins Bcl-2 andBclx/l, together with an increase in the pro-apoptotic protein Bad levels. In addition,the activation of ERK signaling pathway was found to be a requisite for theT44Bf apoptotic activity. Our findings further describe a novel activity for abenzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitoticprototype for the development of chemotherapeutic agents in the treatment ofhematological malignancies.