N′-[4-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide is a dynamin GTPase inhibitor that suppresses cancer cell migration and invasion by inhibiting actin polymerization |
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| Authors: | Hiroshi Yamada Tadashi Abe Shun-Ai Li Shota Tago Peng Huang Masami Watanabe Satoru Ikeda Naohisa Ogo Akira Asai Kohji Takei |
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| Affiliation: | 1. Department of Neuroscience, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-Cho, Kita-ku, Okayama 700-8558, Japan;2. Department of Urology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-Cho, Kita-ku, Okayama 700-8558, Japan;3. Department of Medical Technology, Graduate School of Health Sciences, Okayama University, 2-5-1, Shikata-Cho, Kita-ku, Okayama 700-8558, Japan;4. Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan;5. CREST, JST, 2-5-1, Shikata-Cho, Kita-ku, Okayama 700-8558, Japan |
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| Abstract: | Dynasore, a specific dynamin GTPase inhibitor, suppresses lamellipodia formation and cancer cell invasion by destabilizing actin filaments. In search for novel dynamin inhibitors that suppress actin dynamics more efficiently, dynasore analogues were screened. N′-[4-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide (DBHA) markedly reduced in vitro actin polymerization, and dose-dependently inhibited phosphatidylserine-stimulated dynamin GTPase activity. DBHA significantly suppressed both the recruitment of dynamin 2 to the leading edge in U2OS cells and ruffle formation in H1299 cells. Furthermore, DBHA suppressed both the migration and invasion of H1299 cells by approximately 70%. Furthermore, intratumoral DBHA delivery significantly repressed tumor growth. DBHA was much less cytotoxic than dynasore. These results strongly suggest that DBHA inhibits dynamin-dependent actin polymerization by altering the interactions between dynamin and lipid membranes. DBHA and its derivative may be potential candidates for potent anti-cancer drugs. |
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| Keywords: | Dynasore Dynamin Actin cytoskeleton Migration Invasion GTPase |
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