New 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ether Compound Induces Microtubule Depolymerization and Subsequent Apoptosis

Hiromi Sato; Ryota Yamada; Midori Yanagihara; Hiroko Okuzawa; Hiroki Iwata; Ayako Kurosawa; Saki Ichinomiya; Rina Suzuki; Hiroyuki Okabe; Tomohiro Yano; Takuya Kumamoto; Noriyuki Suzuki; Tsutomu Ishikawa; Koichi Ueno

doi:10.1254/jphs.11229FP

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New 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ether Compound Induces Microtubule Depolymerization and Subsequent Apoptosis

Hiromi Sato, Ryota Yamada, Midori Yanagihara, Hiroko Okuzawa, Hiroki Iwata, Ayako Kurosawa, Saki Ichinomiya, Rina Suzuki, Hiroyuki Okabe, Tomohiro Yano, Takuya Kumamoto, Noriyuki Suzuki, Tsutomu Ishikawa, Koichi Ueno

Author information

Hiromi Sato
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Ryota Yamada
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Midori Yanagihara
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Hiroko Okuzawa
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Hiroki Iwata
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Ayako Kurosawa
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Saki Ichinomiya
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Rina Suzuki
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Hiroyuki Okabe
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Tomohiro Yano
Department of Life Environmental Sciences, Faculty of Life Sciences, Toyo University, Japan
Takuya Kumamoto
Faculty of Pharmaceutical Sciences, Musashino University, Japan
Noriyuki Suzuki
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Tsutomu Ishikawa
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Koichi Ueno
Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan

Keywords: naphthoquinone-1-oxime, microtubule depolymerization, cytotoxicity, spindle assembly checkpoint, cell cycle

JOURNAL FREE ACCESS

2012 Volume 118 Issue 4 Pages 467-478

DOI https://doi.org/10.1254/jphs.11229FP

View "Advance Publication" version (March 14, 2012).

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Abstract

In this study, we describe the antitumor activity of QO-1, one of the new 2-aryl-1,4-naphthoquinone-1-oxime methyl ether derivatives. QO-1 is a derivative of macarpine, a natural occurring product from Rutaceae plant. It could potently inhibit cell growth when tested on 19 cancer cell lines. To investigate its mechanism, two cell lines (HeLa and MCF-7) sensitive to QO-1 were selected. Based on flow cytometry, it was found to induce G₂/M-phase arrest. Moreover, it could cause microtubule depolymerization both in vitro and in vivo. On the other hand, QO-1 activated spindle assembly checkpoint (SAC) proteins. Expression of Bub1, one of the SAC, was gradually increased, reaching a peak after 16 – 20 h, and then gradually decreased. Instead, QO-1 increased the sub-G₁ population, which suggested a cell death population. Actually, expression of Bcl-2 family proteins and activation of caspase-3/7 were evidences of apoptosis. Consistent with these results, cells with DNA fragmentation and multinucleated cells were increased time-dependently after QO-1 exposure. In conclusion, QO-1 has promising antitumor effects via microtubule depolymerization.

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