title: α-Hederin Induces Apoptosis, Membrane Permeabilization and Morphologic Changes in Two Cancer Cell Lines Through a Cholesterol-Dependent Mechanism.
abstract: In perspective of reducing the mortality of cancer, there is a high interest in compounds which act on multiple cellular targets and therefore prevent the appearance of cancer resistances. Saponins andα-hederin, an oleanane-type saponin, induce cancer cell death through different pathways, including apoptosis and membrane permeabilization. Unfortunately, the mechanism by which cell death is induced is unknown. We hypothesized that the activity ofα-hederin mainly depends on its interaction with membrane cholesterol and therefore investigated the cholesterol and saponin-structure dependency of apoptosis and membrane permeabilization in two malignant monocytic cell lines. Apoptotic cell death and membrane permeabilization were significantly reduced in cholesterol-depleted cells. Permeabilization further depended upon the osidic side chain ofα-hederin and led to extracellular calcium influx and nuclear fragmentation, with only the latter being susceptible to caspase inhibitors. Membrane order, measured by laurdan generalized polarization imaging, was neither reduced byα-hederin nor its aglycone hederagenin suggesting that their activity was not related to membrane cholesterol extraction. However, a radical change in morphology, including the disappearance of pseudopodes was observed upon incubation withα-hederin. Our results suggest that the different activities ofα-hederin mainly depend on its interaction with membrane cholesterol and consequent pore formation.
authors: Université catholique de Louvain, Louvain Drug Research Institute, Cellular and Molecular Pharmacology, Bruxelles, Belgium.
authors: Joseph H
authors: JH
authors: Lorent
authors: Université catholique de Louvain, Louvain Drug Research Institute, Cellular and Molecular Pharmacology, Bruxelles, Belgium.
authors: Catherine
authors: C
authors: Léonard
authors: Université catholique de Louvain, Louvain Drug Research Institute, Cellular and Molecular Pharmacology, Bruxelles, Belgium.
authors: Marthe
authors: M
authors: Abouzi
authors: Université catholique de Louvain, Louvain Drug Research Institute, Cellular and Molecular Pharmacology, Bruxelles, Belgium.
authors: Farida
authors: F
authors: Akabi
authors: Université catholique de Louvain, Louvain Drug Research Institute, Pharmacognosy, Bruxelles, Belgium.
authors: Joëlle
authors: J
authors: Quetin-Leclercq
authors: Université catholique de Louvain, Louvain Drug Research Institute, Cellular and Molecular Pharmacology, Bruxelles, Belgium.
authors: Marie-Paule
authors: MP
authors: Mingeot-Leclercq
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002784:Cholesterol / Q000737:chemistry; D006801:Humans; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012503:Saponins / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D012503:Saponins; C010177:beta-hederin; D009828:Oleanolic Acid; D002784:Cholesterol; D002118:Calcium