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

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

来源：Journal of Pharmacological Sciences, 2012, 118(4): 467-478.

DOI：10.1254/jphs.11229FP

• naphthoquinone-1-oxime
• microtubule depolymerization
• cytotoxicity
• spindle assembly checkpoint
• cell cycle

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 G(2)/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-G, 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.

• 出版日期2012-4