Once a crucial element in the medical repertoire of Hippocrates for successfully treating infections like malaria, syphilis and yaws, arsenic is also an effective treatment for certain types of leukemia, or cancer of white blood cells. Long-term exposure to arsenic in drinking water, however, has been linked to cancer of the bladder, lungs, skin, kidney, nasal passages, liver and prostate.
"Arsenic has dual effects depending on the background; in normal cells it can cause cancer, and in cancerous cells it can lead to cell death. We have found one mechanism that may explain both of these effects," says Chi V. Dang, M.D., professor and director of hematology at Hopkins and co-author of the paper.
Specifically, Dang and his team found that arsenic inhibits transcription of a gene, hTERT, that in turn inhibits the expression of telomerase, an enzyme that protects the ends of chromosomes. Low levels of telomerase cause end-to-end fusions of chromosomes, which promote genetic instability. This instability may then lead to cancer in healthy cells and apoptosis, or cell death, in cancerous cells, according to Dang.
The Hopkins researchers report their findings in the current issue of The Journal of Clinical Investigation.
Serendipity had much to do with the discovery, according to Dang. While investigating how cancer cells react to arsenic, one of the researchers, Wen-Chien Chou, a graduate student in human genetics and molecular biology at Hopkins, noticed that some of the cells were abnormally large and tended to die sooner than expected. They then found that these big cells also had end-to-end fusion of their chromosomes, suggesting that arsenic was somehow causing genetic instability.
"It didn't take long to put two and two together," says Dang. "Once we saw the fused chromosomes we knew that telomerase might be responsible. So we did a very direct experiment that asked: Does arsenic inhibit telomerase? The answer is absolutely yes. Cells exposed to arsenic exhibit a dramatic inhibition of telomerase."
The findings have implications for both the development of therapies for treating cancer and for larger public health issues relating to acceptable levels of arsenic in drinking water.
"We've provided evidence that arsenic causes genetic instability potentially leading to cancer," says Dang. "This provides an underlying scientific reason for why we don't want high levels of arsenic in our drinking water." The World Health Organization (WHO), the Department of Health and Human Services (DHHS), and the EPA have determined that arsenic is carcinogenic to humans.
The results could also lead to development of more effective chemotherapy to treat leukemia. Studies in China and elsewhere have shown that the compound arsenic trioxide is very effective in treating acute promyelocytic leukemia (APL), a variant of acute myeloid leukemia that accounts for 10 percent to 15 percent of this cancer in adults, according to Dang.
"Chemotherapy works by attacking a number of different weak points of a cancer cell," says Dang. "Our findings put into perspective how arsenic can be used in combination with other drugs in chemotherapy to fight cancer."
Arsenic is a naturally occurring element found throughout the earth's crust and also in water, air, plants and animals. It is released into the environment through natural geological processes such as volcanism, erosion of rocks, forest fires, and through human industrial activity.
The research was supported by the National Institutes of Health.
Chou, Wen-Chien, et al., Arsenic inhibition of telomerase transcription leads to genetic instability. Journal of Clinical Investigation, 2001, vol. 108, no. 10.
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Journal
Journal of Clinical Investigation