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

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

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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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