The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis

Anna-Leena Salmela, Jeroen Pouwels, Anu Kukkonen-Macchi, Sinikka Waris, Pauliina Toivonen, Kimmo Jaakkola, Jenni Mäki-Jouppila, Lila Kallio (Corresponding Author), Marko J. Kallio

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Abstract

The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule–kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3′,5-dihydroxy-4′,6,7-trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule–kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model.

Original languageEnglish
Pages (from-to)578-592
JournalExperimental Cell Research
Volume318
Issue number5
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

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Keywords

  • Aurora B kinase
  • spindle assembly checkpoint
  • mitosis
  • cytokinesis
  • flavonoid
  • eupatorin

Cite this

Salmela, A-L., Pouwels, J., Kukkonen-Macchi, A., Waris, S., Toivonen, P., Jaakkola, K., Mäki-Jouppila, J., Kallio, L., & Kallio, M. J. (2012). The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis. Experimental Cell Research, 318(5), 578-592. https://doi.org/10.1016/j.yexcr.2011.12.014