Arsenite, a compound commonly used in pesticides and glass production, may counter-intuitively work as a treatment for a rare form of cancer, according to a team of Dartmouth researchers led by Dartmouth Medical School instructor of pharmacology and toxicology Sutisak Kitareewan. In an article published in the Jan. 3 edition of the Journal of the National Cancer Institute, the researchers identify a new way by which arsenite, a form of arsenic, can treat acute promyelocytic leukemia by destroying abnormal proteins present within the afflicted cells.
"Arsenic has been used as a therapy for human disease for centuries," said Ethan Dmitrovsky, a co-author on the study and a professor of medicine and of pharmacology and toxicology. "An agent that has a known toxicity may also have therapeutic effects at lower doses."
The form of leukemia, APL, affects about 1,500 to 2,000 people annually in the United States and kills less than 10 percent of them. This type of cancer occurs when sections of chromosomes 15 and 17 are switched. This results in the creation of an abnormal cancer-causing protein that impedes the development of white blood cells, an important part of the immune system. This multiplication of the immature white blood cells leads to leukemia, when the body is unable to generate healthy versions of the cells and cannot fight infection.
"This appears to be due to the oncogenic protein repressing the function of the normal retinoic acid receptor pathway," Dmitrovsky said.
Traditionally, those afflicted by APL are treated with retinoic acid, which destroys the abnormal protein. Many patients, however, develop a resistance to this treatment, necessitating another form of therapy.
The researchers found that treating APL cells with arsenite causes lysosomes -- structures in the cells that contain enzymes -- to release the enzymes and thus destroy the abnormal protein. While it was previously understood that arsenite degrades the protein, this enzymatic mechanism had not been identified.
"We have uncovered this in the lab and we now seek to translate this work back to the in vivo setting of the whole organism, such as animals and even studying the leukemic cells from patients treated with arsenic who have APL," Dmitrovsky said.
B.D. Roebuck, Eugene Demidenko and Roger Sloboda were also contributing authors.
