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

San Carlos de Bariloche

Simposio; The Third American Spring Symposium in Signal Trasduction and Molecular Medicine; 2015

Anti-mitotic therapies have been considered as a hallmark of strategies against abnormal proliferative cells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds, we have previously 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 effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by programmed cell death induction. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to normal peripheral blood mononuclear cells. The underlying mechanism of action involves the activation of the mitochondria signaling pathway, with loss of mitochondrial membrane potential and sustained phosphorylation of anti-apoptotic proteins Bcl-2 and Bclx/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 the T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype for the development of chemotherapeutic agents in the treatment of hematological malignancies.