title: Apoptosis induction by the natural product cancer chemopreventive agent deguelin is mediated through the inhibition of mitochondrial bioenergetics.
abstract: Deguelin exhibits chemopreventive properties in animal carcinogenesis models. The mechanism underpinning the chemopreventive effects of deguelin has not been fully elucidated. However, it has been suggested that this agent reduces ornithine decarboxylase activity, and perhaps the activity of other signaling intermediates associated with tumorigenesis, by inhibiting mitochondrial bioenergetics. We sought to determine if deguelin could trigger apoptosis by inhibiting mitochondrial bioenergetics. Therefore, we compared and contrasted the effects of deguelin on cells from two human cutaneous squamous cell carcinoma cell lines (parental cells) and their respiration-deficient clones lacking mitochondrial DNA (rho0). While deguelin promoted marked apoptosis in the parental cells in a dose- and time-dependent manner, it failed to do so in the rho0 clones. Furthermore, short-term exposure to deguelin diminished oxygen consumption by the parental cells and promoted mitochondrial permeability transition as evidenced by the dissipation of mitochondrial inner transmembrane potential, reactive oxygen species production, cardiolipin peroxidation, caspase activation, and mitochondrial swelling. Mitochondrial permeability transition was not observed in the rho0 clones exposed to deguelin. These results demonstrate that deguelin induces apoptosis in skin cancer cells by inhibiting mitochondrial bioenergetics and provide a novel mechanism for the putative anticancer activity of this agent.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. nhail@mdanderson.org
authors.forename: N
authors.initials: N
authors.lastname: Hail
authors.forename: R
authors.initials: R
authors.lastname: Lotan
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002308:Cardiolipins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003585:Cell Biology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008858:Microscopy, Phase-Contrast; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D002308:Cardiolipins; D004272:DNA, Mitochondrial; D014475:Uncoupling Agents; D012402:Rotenone; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D020169:Caspases; C107676:deguelin