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

Hong, JangJa; Yokomakura, Aya; Nakano, Yasuhiro; Ishihara, Kenji; Kaneda, Makoto; Onodera, Mitsue; Nakahama, Ken-ichi; Morita, Ikuo; Niikura, Kazuaki; Ahn, Jong-Woong; Zee, OkPyo; Ohuchi, Kazuo

Abstract: Apicularen A and the known vacuolar-type (H )-ATPase (V-ATPase) inhibitor bafilomycin A1 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 A1-sensitive ATP hydrolysis. The IC50 values of the proton transport were 0.58nM for apicularen A, 13nM for apicularen B, and 0.95nM for bafilomycin A1. Furthermore, apicularen A inhibited the bafilomycin A1-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.

ADENOSINE triphosphatase; APOPTOSIS; HYDROLYSIS; GLUCOSAMINE

FEBS Letters, 2006, Vol 580, Issue 11, p2723

0014-5793

Academic Journal

10.1016/j.febslet.2006.04.031