Target Identification and Mode of Action Studies of an Antitumor Compound Aplyronine A by Using Photoaffinity Derivatives

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  • Kita Masaki
    Faculty of Pure and Applied Sciences, University of Tsukuba
  • Kigoshi Hideo
    Faculty of Pure and Applied Sciences, University of Tsukuba

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  • 光親和性プローブを用いた抗腫瘍性天然物アプリロニンAの標的分子と作用機序の研究
  • ヒカリ シンワセイ プローブ オ モチイタ コウシュヨウセイ テンネンブツ アプリロニン A ノ ヒョウテキ ブンシ ト サヨウ キジョ ノ ケンキュウ

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Abstract

Actin is an essential cytoskeletal protein for the regulation of various cellular functions. A number of actin-stabilizing and depolymerizing agents have been discovered in marine invertebrates, and they show potent cytotoxicity. Among them, a polyketide macrolide aplyronine A has antitumor effects against xenograft in mice. However, the potent cytotoxicity and apoptogenic effect of aplyronine A was not entirely accounted for by its actin filament-severing properties, and its molecular targets and mechanisms of action remained unclear. We developed aplyronine A acetylene or biotin derivatives that bear an aryldiazirine group at the C34 terminus, which formed a covalent bond with actin. By using these chemical probes, we have showed that aplyronine A synergistically binds to tubulin in association with actin, and prevents spindle formation and mitosis in tumor cells. Our findings of aplyronine A will provide further insights into the molecular mechanisms of structurally diverse natural products that regulate cytoskeletal dynamics.

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