G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound

MAIA CABRERA, NATALIA GOMEZ, FEDERICO REMES LENICOV, EMILIANA ECHEVERRÍA, CARINA SHAYO, ALBERTINA MOGLIONI, NATALIA FERNÁNDEZ, CARLOS DAVIO

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2015

1932-6203

Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferatingcells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds,we have previously identified 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 antiproliferativeeffects are associated with a reversible chronicmitotic arrest caused by defects in chromosomealignment, followed by induced programmed cell death. Furthermore, T44Bf selectivelyinduces apoptosis in leukemia cell lines when compared to normal peripheral bloodmononuclearcells. The underlying mechanismof action involves the activation of themitochondria signalingpathway, with loss ofmitochondrialmembrane potential and sustained phosphorylationof anti-apoptotic protein Bcl-xL as well as increased Bcl-2 (enhanced phosphorylated fraction)and pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was foundto be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for abenzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype todevelop chemotherapeutic agents to treat acute leukemia malignancies.