title: Novel genistein derivatives induce cell death and cell cycle arrest through different mechanisms.
abstract: Genistein is a natural compound belonging to isoflavone family of secondary plant metabolites, characterized by pleiotropic biological activity. Here we present the results of a study on new analogs and polysaccharide complexes of genistein as potent antiproliferative and cell death-inducing agents. Most potent were 2 analogs (i.e., IFG-027 and IFG-043) and 2 complexes (i.e., SPG-G and XG-G), which had higher or similar antiproliferative activity in comparison to genistein. However, these 2 analogs decreased the number of cells in G2/M phase in contrast to genistein and SPG-G complex. Genistein analogs, IFG-027 and IFG-043, and also SPG-G complex decreased mitochondrial membrane potential and induced the externalization of phosphatidylserine to the extracellular membrane site, which indicates the induction of apoptosis. Interestingly, genistein and its analogs induced caspase 3-activation supporting apoptotic mechanism of cell death but SPG-G supported caspase 3-independent apoptosis. XG-G complex probably did not induce cell death through the apoptotic pathway, as we did not find the externalization of phosphatidylserine and activation of caspase-3. After the treatment of HL-60 cells with genistein, SPG-G and XG-G formation of acidic vesicular organelle (AVO) was detected. In contrast, in the cells that were treated with genistein analogs IFG-027 and IFG-043, AVO formation was not observed.
authors.affiliation: Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Wrocław, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Switalska
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Grynkiewicz
authors.forename: Leon
authors.initials: L
authors.lastname: Strzadala
authors.forename: Joanna
authors.initials: J
authors.lastname: Wietrzyk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D041702:BALB 3T3 Cells; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019833:Genistein / Q000031:analogs & derivatives / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*
chemical_list: D010936:Plant Extracts; D019833:Genistein; C505407:CASP3 protein, human; D053148:Caspase 3