ARSENIC TRIOXIDE MECHANISM OF ACTION IN APL REVEALED

SINGAPORE (Reuters) Apr 09 - Scientists in China have demonstrated how arsenic can treat leukemia by targeting and killing specific proteins that keep the cancer alive.

"Our study showed how arsenic directly targets these proteins and kills them," lead researcher Dr. Zhang Xiaowei at the State Key Laboratory of Medical Genomics in Shanghai, China, told Reuters.

"Unlike chemotherapy, the side effects of arsenic (in treating acute promyelocytic leukemia) are very low. There is no hair loss or suppression of bone marrow (function). We are interested in finding out how arsenic can be used in other cancers," Dr. Zhang said by telephone.

Well known for its toxicity, arsenic was regarded in the past as the king among poisons because its symptoms are like those of cholera and can often go undetected.

In China, however, it has long served a dual purpose. Apart from intentional poisoning, it has been used for at least 2,000 years in traditional Chinese medicine.

In 1992, a group of Chinese doctors reported how they used arsenic to treat acute promyelocytic leukemia (APL), which has surprisingly high cure rates of over 90% in China.

However, the actual workings of arsenic and how it interacts with cancer has never been clear -- until Dr. Zhang and his colleagues used modern technology to find out.

In a paper published April 9th in Science, Dr. Zhang and his team, which includes Health Minister Chen Zhu, reported that arsenic attacked specific proteins that would otherwise be keeping the cancer alive and well.

"This shows how Western technology can be used to find out about the mysteries of Chinese medicine," Dr. Zhang said.

According to the researchers' article, arsenic promotes degradation of an oncogenic protein that drives the growth of APL cells. This protein, PML-RAR alpha, is a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha. The investigators discovered that arsenic binds directly to cysteine residues in the zinc fingers. Arsenic binding induces oligomerization of PML, "which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation," the researchers report.

They add, "The identification of PML as a direct target of (arsenic) provides new insights into the drug's mechanism of action and its specificity for APL."

"Although many countries are now using arsenic to treat APL, some countries are resistant to the idea. It depends a lot on whether doctors recommend it and whether patients accept it," Dr. Zhang said.

The clinical result of arsenic in treating APL is well-established, with 5-year disease-free survival of more than 90% of APL patients in China, he added..

In a separate commentary in Science, Dr. Scott Kogan at the University of California San Francisco Cancer Center wrote that proper case selection and combination therapy with arsenic may lead to improved outcomes for treating not only promyelocytic leukemia, but other diseases as well.

"If so, an ancient medicine, revived through careful clinical and biological studies in modern times, will have an even greater impact on human health," wrote Dr. Kogan.

Science 2010;328:240-243.