title: G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound.
abstract: Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. 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 antiproliferative effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by induced programmed cell death. 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 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 found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype to develop chemotherapeutic agents to treat acute leukemia malignancies.
authors.affiliation: Instituto de Investigaciones Farmacológicas, Facultad de Farmacia y Bioquímica (ININFA-UBA-CONICET), Buenos Aires, Argentina.
authors.forename: Maia
authors.initials: M
authors.lastname: Cabrera
authors.affiliation: Instituto de Investigaciones Farmacológicas, Facultad de Farmacia y Bioquímica (ININFA-UBA-CONICET), Buenos Aires, Argentina; Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gomez
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Facultad de Medicina, (INBIRS-UBA-CONICET), Buenos Aires, Argentina.
authors.forename: Federico
authors.initials: F
authors.lastname: Remes Lenicov
authors.affiliation: Instituto de Investigaciones Farmacológicas, Facultad de Farmacia y Bioquímica (ININFA-UBA-CONICET), Buenos Aires, Argentina.
authors.forename: Emiliana
authors.initials: E
authors.lastname: Echeverría
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.
authors.forename: Carina
authors.initials: C
authors.lastname: Shayo
authors.affiliation: Instituto de Química y Metabolismo del Fármaco, Facultad de Farmacia y Bioquímica, (IQUIMEFA-UBA-CONICET), Buenos Aires, Argentina; Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Albertina
authors.initials: A
authors.lastname: Moglioni
authors.affiliation: Instituto de Investigaciones Farmacológicas, Facultad de Farmacia y Bioquímica (ININFA-UBA-CONICET), Buenos Aires, Argentina; Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández
authors.affiliation: Instituto de Investigaciones Farmacológicas, Facultad de Farmacia y Bioquímica (ININFA-UBA-CONICET), Buenos Aires, Argentina; Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Davio
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001577:Benzophenones / Q000737:chemistry; D015415:Biomarkers; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056750:Cyclin A1 / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; D015415:Biomarkers; D056750:Cyclin A1; D056744:Cyclin B1; D013882:Thiosemicarbazones; C047723:benzophenone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3