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Published on: January 1, 2017
Iejimalides show anti-osteoclast activity via V-ATPase inhibition
Sayaka Kazami1, Makoto Muroi, Makoto Kawatani
1Antibiotics Laboratory, RIKEN Discovery Research Institute, Hirosawa, Saitama.
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.
Insights
Iejimalides (IEJLs) are new vacuolar H(+)-ATPase (V-ATPase) inhibitors. These compounds show antitumor and antiosteoporotic effects by blocking V-ATPase activity in cells.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Iejimalides (IEJLs) are potent antitumor macrolides with unknown molecular targets.
- Osteoclasts play a role in bone resorption and are sensitive to vacuolar H(+)-ATPase (V-ATPase) inhibitors.
Purpose of the Study:
- To identify the molecular targets of Iejimalides (IEJLs).
- To investigate the potential of IEJLs as V-ATPase inhibitors for antitumor and antiosteoporotic therapies.
Main Methods:
- Screening IEJLs for biological activity.
- Testing IEJLs' inhibitory effects on mammalian and yeast V-ATPases in situ and in vitro.
- Utilizing a bafilomycin-resistant yeast mutant to assess IEJLs' binding site.
Main Results:
- IEJLs were identified as potent osteoclast inhibitors.
- IEJLs demonstrated inhibition of V-ATPases in both mammalian and yeast cells.
- A yeast mutant resistant to bafilomycin also showed resistance to IEJLs, indicating a similar binding site.
Conclusions:
- IEJLs are novel inhibitors of V-ATPases.
- The antitumor and antiosteoporotic activities of IEJLs are mediated through V-ATPase inhibition.
