For the last few years, scientists have puzzled over arsenic's apparently paradoxical ability to both cause and cure cancer. Now they have a new explanation for the chemical's effects: Arsenic forces the cell's chromosomes to clump together, which can disrupt DNA in normal cells and leave them multiplying out of control; it can also provoke already cancerous cells to self destruct. The results may suggest new possibilities for cancer-fighting drugs.
Studies conducted in China and the United States demonstrated that arsenic--long considered a carcinogen--helps treat a blood cancer called acute promyelocytic leukemia. But why arsenic worked defied explanation. Some said that it caused oxygen molecules to become reactive and turn off cancer genes. Others theorized that it broke apart a key protein complex important in cancer pathogenesis. But these mechanisms, though considered solid, failed to account for arsenic's darker side.
The chemical's disruptive effects on chromosomes may explain its split personality, Chi Dang and his colleagues at Johns Hopkins School of Medicine in Baltimore report in the November issue of the Journal of Clinical Investigation. Studying acute promyelocytic leukemia cells under a microscope, the researchers noticed that they become abnormally large in the presence of arsenic. Further examination revealed that the chromosomes were clumping together by fusing at the ends, thereby stretching the cell.
Dang's team traced the clumping back to malfunctions in the enzyme telomerase, which maintains the caps at the ends of the chromosomes and keeps the chromosomes apart from one another. Arsenic, the researchers found, stops a gene for an important part of the telomerase enzyme, known as the reverse transcriptase subunit, from being translated. With arsenic forcing the production of largely useless telomerase in cell lines that simulate acute promyelocytic leukemia, the chromosomes in cancer cells fuse together, causing the cell death that helps fight the cancer. But in healthy cells, the genetic disruption triggered by chromosome clumping either kills the cell or coerces it into multiplying nonstop, causing cancer. Preliminary evidence suggests that arsenic may have the same effect on telomerase in other cancers; human trials are ongoing.
Scientists say that the findings are exciting because, though disrupting telomerase has looked like a good strategy for treating cancer, it's been difficult to pinpoint compounds that do so. The results are "really novel," says cancer researcher Jonathan Licht at the Mount Sinai Cancer Center in New York City. "You have yet another therapeutic mechanism for treating cancer."