Aneuploidy is a chromosomal disorder characterised by abnormal (i.e. neither haploid nor diploid) chromosome number. It occurs when chromosomes do not segregate correctly in cell division and it is a common cause of genetic defects. In humans, aneuploidy of any chromosome other than numbers 13, 18 or 21 results in death during embryonic development. Individuals born with an extra copy of either chromosome 13 ( trisomy 13 or Patau syndrome) or chromosome 18 (Edwards syndrome) usually die in infancy; trisomy of chromosome 21, the smallest human chromosome, causes Down syndrome. Aneuploidy at the cellular level can cause cellular stress and defects in cell proliferation.

Many human cancer cells are known to be aneuploid, and studies in mouse models have indicated this to be one of the drivers of tumour development. This suggests that molecules that selectively target the cellular stresses and metabolic changes characteristic of aneuploid cells might be useful as anti-cancer drugs. A group led by Angelika Amon at Massachusetts Institute of Technology, Cambridge, MA, USA has now identified three such compounds and elucidated some of their mechanisms of action.

Amon and her co-workers used models of mouse embryonic fibroblasts (MEFs) that are trisomic for any of the mouse chromosomes 1, 13, 16 or 19: these chromosomes were chosen to span the range of chromosome size and gene number present in the mouse. They tested the effect of compounds known to cause genotoxic stress, proteotoxic stress or energy stress on cell growth and number in each of these cell lines. Most compounds either did not affect the proliferation of trisomic MEFs or did so only in a few cases. Three compounds were found to impair the accumulation MEFs carrying all four trisomies tested: AICAR, an energy stress inducer; 17-AAG, an inhibitor of the chaperone Hsp90; and chloroquine, an autophagy inhibitor used as a malaria prophylactic. Cells containing an extra copy of the largest mouse chromosome, chromosome 1, tended to be more sensitive than those trisomic for the smaller chromosomes, and combinations of AICAR with either 17-AAG or chloroquine were more effective in reducing cell proliferation than any of the compounds alone.

These compounds were found to reduce the numbers of trisomic MEF cells by inducing cell cycle arrest and apoptosis; this mechanism did not occur with normal (euploid) cells of the same type. The researchers then explored the question of the mechanisms through which the compounds operate. They found that AICAR activates the kinase AMPK, which is an activator of the tumour suppressor p53, and suggested that p53 activates apoptosis in the trisomic cells. Since other AMPK activators fail to induce apoptposis selectively in trisomic cells, this compound must also act through additional mechanisms, thought to be through increasing the general cellular stress caused by the extra chromosome. Both 17-AAG and chloroquine were also found to induce apoptosis through p53-mediated mechanisms.

This study uses cell models involving the addition of a single chromosome to model the more complex aneuploidies present in cancer cells. To test the validity of this model, the researchers tested the three compounds against several human solid tumour cell lines, some containing many chromosome number abnormalities and others near normal in this respect. They found that AICAR and 17-AAG, but not chloroquine, showed significant anti-proliferative activity in the aneuploid cell lines, and that these two compounds together had a stronger effect still. Interestingly, however, colon cancer cells were more sensitive than lung cancer cells, and the effect was seen in aneuploid cell lines with both wild-type and mutated p53.17-AAG is already under clinical investigation as a drug for both multiple myeloma and anaplastic large cell lymphoma; these results suggest that this and other compounds that selectively target aneuploid cells may be effective against solid tumours, either alone or more likely in combination.

Source: Tang, Y-C., Williams, B.R., Siegel, J.J. and Amon, A. (2011). Identification of Aneuploidy-Selective Antiproliferation Compounds. Cell 144, 499–512. doi: 10.1016/j.cell.2011.01.017