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

Oncotarget. 2014 Sep 30;5(18):8379-92. doi: 10.18632/oncotarget.2292.

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.

Publication types

  • Video-Audio Media

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • CDC2 Protein Kinase
  • Cell Survival / drug effects
  • Centrosome / drug effects*
  • Centrosome / metabolism
  • Cyclin B1 / metabolism
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Enzyme Activation
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • Hep G2 Cells
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • MCF-7 Cells
  • Microtubules / drug effects*
  • Microtubules / metabolism
  • Mitosis / drug effects*
  • Podophyllotoxin / analogs & derivatives*
  • Podophyllotoxin / pharmacology
  • RNA Interference
  • Receptors, Somatomedin / genetics
  • Receptors, Somatomedin / metabolism*
  • Signal Transduction / drug effects*
  • Time Factors
  • Transfection
  • Tubulin / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • CCNB1 protein, human
  • Cyclin B1
  • IGF1R protein, human
  • Receptors, Somatomedin
  • Tubulin
  • picropodophyllin
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • Podophyllotoxin