Response of experimental malignant melanoma models to the pan-Aurora kinase inhibitor VE-465

Exp Dermatol. 2010 Dec;19(12):1040-7. doi: 10.1111/j.1600-0625.2010.01182.x.


Aurora kinases represent promising novel cancer therapy targets. Genomic analyses of human cutaneous melanoma (CMM) models (N = 51, low passage) by classical and/or array CGH revealed frequent gains at chromosome 20q (65%, amplifications in 45%) repeatedly including the Aurora A gene locus. Accordingly, the majority of CMM cell cultures overexpressed Aurora A when compared to proliferating non-malignant cells. Moreover, CMM cells even when arrested in G1/S cell cycle phase contained readily detectable levels of Aurora A indicating incomplete degradation during mitosis. Already at low concentrations (10-100 nm), long-term (7-10 days) application of the pan-Aurora kinase inhibitor VE-465 completely prevented colony formation in all CMM models tested. In contrast, blockade of cell survival/proliferation and DNA synthesis as well as the induction of apoptosis by VE-465 distinctly differed in short-term experiments (up to 72 h exposure). Both cell cycle arrest and DNA synthesis blockade depended on the level of VE-465-mediated p53/p21 activation while p53/p21 unresponsiveness led to repetitive endoreduplication (>8n DNA content). In contrast, apoptosis induction by VE-465 and Aurora A siRNA did not correlate with p53/p21 responsiveness and DNA synthesis blockade. Moreover, application of the Aurora B-specific inhibitor ZM447439 and siRNA was less efficient to induce CMM cell death proofing that apoptosis induction by VE-465 depended predominantly on Aurora A targeting. In combination experiments with chemotherapeutic agents, VE-465 acted additive to antagonistic when applied concomitantly but in several cases even synergistic when applied consecutively. In summary, we suggest that the Aurora A kinase might represent a promising target of well-designed novel antimelanoma strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Aurora Kinase B
  • Aurora Kinases
  • Caspase 7 / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chromosomes, Human / genetics
  • Drug Synergism
  • Gene Amplification / genetics
  • HCT116 Cells
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / enzymology
  • Melanoma / genetics
  • Melanoma / pathology*
  • Neoplastic Stem Cells / drug effects
  • Piperazines / pharmacology*
  • Polyploidy
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Tumor Cells, Cultured / drug effects
  • Tumor Suppressor Protein p53 / metabolism


  • Piperazines
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • VX680
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Caspase 7