Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism
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Ahmed Waraky1, Karen Akopyan2, Vendela Parrow3, Thomas Strömberg1, Magnus Axelson4, Lars Abrahmsén3, Arne Lindqvist2, Olle Larsson1 and Eiman Aleem1,5,6
1 Department of Oncology-Pathology, Cancer Center Karolinska, Solna, Sweden
2 Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden
3 Axelar AB, Karolinska Institutet Science Park, Solna, Sweden
4 Department of Clinical Chemistry, Karolinska Institutet, Stockholm, Sweden
5 Alexandria University, Faculty of Science, Department of Zoology, Alexandria, Egypt
6 The Ronald A. Matricaria Institute of Molecular Medicine at Phoenix Children’s Hospital, University of Arizona College of Medicine-Phoenix, Department of Child Health, Phoenix, Arizona, USA
Correspondence:Eiman Aleem, email: email@example.com
Keywords: Picropodophyllin, mitotic arrest, CDK1, IGF-1R, mitotic catastrophe
Received: May 14, 2014 Accepted: July 31, 2014 Published: July 31, 2014
Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated.
The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues.
Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics.
These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP.
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