Oncotarget

Research Papers:

Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism

Ahmed Waraky, Karen Akopyan, Vendela Parrow, Thomas Strömberg, Magnus Axelson, Lars Abrahmsén, Arne Lindqvist, Olle Larsson and Eiman Aleem _

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Oncotarget. 2014; 5:8379-8392. https://doi.org/10.18632/oncotarget.2292

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Abstract

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: ealeem@email.arizona.edu

Keywords: Picropodophyllin, mitotic arrest, CDK1, IGF-1R, mitotic catastrophe

Received: May 14, 2014 Accepted: July 31, 2014 Published: July 31, 2014

Abstract

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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