Arsenic makes a comeback

Combining arsenic and bryostatin destroys leukemic cells and the duo therapy also shows less toxicity

By Graham Furmess

Arsenic isn't something that immediately springs to mind when one considers promising new medicines. But it has been used to treat cancer in China since the time of the Communist revolution and it's been a component of Chinese medicine for centuries.

In reality, arsenic is no more toxic than many cancer chemotherapeutic drugs used in the West, and it's known to be effective against treatment-resistant acute promyelocytic leukemia (APL), a cancer of the blood and bone marrow, characterized by unhealthy myeloid or white blood cells.

Now, researchers at Johns Hopkins Kimmel Cancer Center [BDW1] have identified the mechanism by which arsenic kills cancer cells, using molecular studies to track the poison's target to NADPH oxidase, an oxygen-producing enzyme complex.

They found that arsenic activates the same cellular self-destruct mechanism as a compound called bryostatin, a toxin found in coral-like aquatic organisms, which is currently attracting interest as a potential treatment for a range of cancers. The findings are published in the March 16 issue of Proceedings of the National Academy of Sciences.

Dr Chi V Dang, lead author of the research, explained the process. "When normal white blood cells engulf invading bacteria, NADPH oxidase produces a big burst of bad reactive oxygen species which they dump into bacteria to kill it and, in the process, kill themselves. We found that in APL, arsenic triggers activation of NADPH oxidase and uses this natural bacteria-killing mechanism against the leukemia cells � in essence, a self-destruct switch."

"But even with arsenic treatment, much of the NADPH oxidase remains dormant in our system," said Dr Dang. That's where bryostatin comes in. This compound, which comes from the secretions of a sea organism called a bryozoan that attaches to boat hulls, rocky surfaces and piers, also kills cancer cells by activating NADPH oxidase. "So, we used bryostatin to wake up the rest of it," added Dr Dang.

"The synergistic effects of combining two drugs that activate the same pathway may allow us to avoid toxicity using lower doses," said researcher Dr Wen-Chien Chou. In fact, doses of the combination arsenic-bryostatin therapy used in the research were one tenth of the doses administered in typical clinical trials testing either drug individually, yet proved effective at killing leukemia cell lines in the laboratory.

Further laboratory and animal research will be necessary before human clinical trials can be conducted. "There's still a question of whether the leukemic cells die by triggering differentiation rather than the oxygen burst, but either way, we're stopping the cells," according to Dr Dang.