Iejimalides Show Anti-Osteoclast Activity via V-ATPase Inhibition

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  • KAZAMI Sayaka
    Antibiotics Laboratory, RIKEN Discovery Research Institute Graduate School of Science and Engineering, Saitama University
  • MUROI Makoto
    Antibiotics Laboratory, RIKEN Discovery Research Institute
  • KAWATANI Makoto
    Antibiotics Laboratory, RIKEN Discovery Research Institute
  • KUBOTA Takaaki
    Graduate School of Pharmaceutical Sciences, Hokkaido University
  • USUI Takeo
    Antibiotics Laboratory, RIKEN Discovery Research Institute
  • KOBAYASHI Jun’ichi
    Graduate School of Pharmaceutical Sciences, Hokkaido University
  • OSADA Hiroyuki
    Antibiotics Laboratory, RIKEN Discovery Research Institute Graduate School of Science and Engineering, Saitama University

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  • Iejimalides Show Anti-Osteoclast Activity<i>via</i>V-ATPase Inhibition

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Abstract

Iejimalides (IEJLs), 24-membered macrolides, are potent antitumor compounds, but their molecular targets remain to be revealed. In the course of screening, we identified IEJLs as potent osteoclast inhibitors. Since it is known that osteoclasts are sensitive to vacuolar H+-ATPase (V-ATPase) inhibitor, we investigated the effect of IEJLs on V-ATPases. IEJLs inhibited the V-ATPases of both mammalian and yeast cells in situ, and of yeast V-ATPases in vitro. A bafilomycin-resistant yeast mutant conferred IEJL resistance, suggesting that IEJLs bind a site similar to the bafilomycins/concanamycins-binding site. These results indicate that IEJLs are novel V-ATPase inhibitors, and that antitumor and antiosteporotic activities are exerted via V-ATPase inhibition.

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