title: Inhibition of vacuolar-type (H+)-ATPase by the cytostatic macrolide apicularen A and its role in apicularen A-induced apoptosis in RAW 264.7 cells.
abstract: Apicularen A and the known vacuolar-type (H(+))-ATPase (V-ATPase) inhibitor bafilomycin A(1) induced apoptosis of RAW 264.7 cells, while apicularen B, an N-acetyl-glucosamine glycoside of apicularen A, was far less effective. Apicularen A inhibited vital staining with acridine orange of the intracellular organelles of RAW 264.7 cells, inhibited the ATP-dependent proton transport into inside-out microsome vesicles, and inhibited the bafilomycin A(1)-sensitive ATP hydrolysis. The IC(50) values of the proton transport were 0.58 nM for apicularen A, 13 nM for apicularen B, and 0.95 nM for bafilomycin A(1). Furthermore, apicularen A inhibited the bafilomycin A(1)-sensitive ATP hydrolysis more potently than apicularen B. F-ATPase and P-ATPase were not inhibited by apicularen A. We concluded that apicularen A inhibits V-ATPase, and thus induces apoptosis in RAW 264.7 cells.
authors.affiliation: Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba Aramaki, Sendai, Miyagi 980-8578, Japan.
authors.forename: JangJa
authors.initials: J
authors.lastname: Hong
authors.forename: Aya
authors.initials: A
authors.lastname: Yokomakura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakano
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishihara
authors.forename: Makoto
authors.initials: M
authors.lastname: Kaneda
authors.forename: Mitsue
authors.initials: M
authors.lastname: Onodera
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nakahama
authors.forename: Ikuo
authors.initials: I
authors.lastname: Morita
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Niikura
authors.forename: Jong-Woong
authors.initials: JW
authors.lastname: Ahn
authors.forename: OkPyo
authors.initials: O
authors.lastname: Zee
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohuchi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D018942:Macrolides; C117813:apicularen A; C117814:apicularen B; C040929:bafilomycin A1; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases