Development of hemiasterlin derivatives as potential anticancer agents that inhibit tubulin polymerization and synergize with a stilbene tubulin inhibitor

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• 作者：Lih-Ching Hsu (1) lhsu@ntu.edu.tw
  David E. Durrant (2)
  Ching-Chun Huang (1)
  Nai-Wen Chi (3)
  Riccardo Baruchello (4)
  Riccardo Rondanin (4)
  Cinzia Rullo (4)
  Paolo Marchetti (4)
  Giuseppina Grisolia (4)
  Daniele Simoni (4)
  Ray M. Lee (5)
• 关键词：Hemiasterlins – ; Stilbene 5c – ; Vincristine – ; Tubulin – ; Anticancer
• 刊名：Investigational New Drugs
• 出版年：2012
• 出版时间：August 2012
• 年：2012
• 卷：30
• 期：4
• 页码：1379-1388
• 全文大小：809.1 KB
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• 作者单位：1. School of Pharmacy, National Taiwan University, 12F, No. 1, Section 1, Jen-Ai Road, Taipei, 10051 Taiwan2. Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA3. Research Service, VA San Diego Healthcare System, School of Medicine, University of California, San Diego, La Jolla, CA, USA4. Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy5. Lestoni Corp, Richmond, VA, USA
• ISSN：1573-0646

文摘

Hemiasterlins are cytotoxic tripeptides with antimicrotubule activity originally isolated from marine sponges. We have developed new hemiasterlin derivatives BF65 and BF78 that are highly potent to induce cancer cell death in the low nanomolar range. Examination of their mechanisms of cell cycle arrest and disruption of microtubules revealed an unusual characteristic in addition to anti-tubulin effect. Immunofluorescence staining revealed that A549 lung carcinoma cells treated with BF65 or BF78 exhibited both monopolar and multipolar mitotic spindles. Centrosomes were separated with short spindle microtubules in cells with multipolar spindles. In vitro tubulin polymerization assay confirmed that both BF65 and BF78 were highly potent to inhibit tubulin polymerization. These two compounds induced the formation of monoastral spindles suggesting that they might be inhibitors of mitotic kinesins such as KSP/Eg5. However, kinetic measurement of microtubule activated kinesin ATPase activity demonstrated that unlike the positive control monastrol, neither BF65 nor BF78 suppressed KSP/Eg5 activity. Hence the effect may be a variant form of tubulin inhibition. Similar to vinca alkaloids, BF compounds synergized with a colchicine site microtubule inhibitor stilbene 5c both in vitro and in vivo, which may provide a potential drug combination in the future clinical application.