title: Deguelin inhibits expression of IkappaBalpha protein and induces apoptosis of B-CLL cells in vitro.
abstract: We investigated if deguelin, a naturally occurring rotenoid, was able to inhibit nuclear factor kappa B (NF-kappaB)-binding protein (IkappaBalpha) expression and to induce apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells in vitro. Deguelin-induced cell death in the majority of B-CLL cells and was found to be more toxic toward B-CLL cells than to the normal mononuclear or B-cells, suggesting selectivity towards the malignant cells. Deguelin was found to reduce IkappaBalpha protein expression, and thus interacts with the NFkappaB pathway. The induced apoptosis was characterized by processing of caspase-9 and -3 and poly-(ADP)-ribose-polymerase cleavage. Exposure of B-CLL cells to deguelin resulted in Bcl2-associated protein (Bax) conformational changes and downregulation of the key survival protein myeloid cell leukemia sequence 1 (Mcl-1), which is associated with response to treatment in B-CLL patients. Deguelin retained its ability to induce apoptosis in B-CLL cells in the presence of interleukin-4, a pro-survival cytokine in B-CLL, and when cultured with 50% human serum. These data indicate that deguelin is able to induce apoptosis in B-CLL cells in the presence of pro-survival signals and thus merits further investigation for clinical application either as a single agent or in combination with other anticancer agents.
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Geeraerts
authors.forename: B
authors.initials: B
authors.lastname: Vanhoecke
authors.forename: W
authors.initials: W
authors.lastname: Vanden Berghe
authors.forename: J
authors.initials: J
authors.lastname: Philippé
authors.forename: F
authors.initials: F
authors.lastname: Offner
authors.forename: D
authors.initials: D
authors.lastname: Deforce
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007306:Insecticides / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D020672:I-kappa B Proteins; D007306:Insecticides; C000606204:NFKBIA protein, human; D012402:Rotenone; D000072000:NF-KappaB Inhibitor alpha; D015847:Interleukin-4; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; C107676:deguelin