Discovery of the mechanism through which arsenic therapy acts against acute promyelocytic leukemia suggests that a combination of arsenic and a natural toxin may be highly effective, according to an article in the March 16th issue of the Proceedings of the National Academy of Sciences.

Used for centuries for a variety of medicinal purposes, arsenic was first used as therapy for cancer in post-revolution China and is known to be effective against treatment-resistant acute promyelocytic leukemia (APL). In the current research, American investigators used APL cell lines to study the mechanism through which arsenic acts as a cytotoxin. With use of molecular studies, the researchers found that arsenic acts against NADPH oxidase, a critical oxygen-producing enzyme complex.

When the researchers realized the arsenic target was the same as the target attacked by bryostatin, a toxin found in coral-like aquatic organisms, they used a low-dose combination of bryostatin and arsenic and found it effective against the APL cells.

"When normal white blood cells engulf invading bacteria, NADPH oxidase produces a big burst of bad oxygen species which they dump into bacteria to kill it and, in the process, kill themselves," said Chi V. Dang, MD, PhD, a coauthor of the study. "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."

Dang explained, "Even with arsenic treatment, much of the NADPH oxidase remains dormant in our system." However, previous molecular studies showed that NADPH oxidase also is activated by bryostatin, which is currently under clinical investigation for a wide variety of cancers. In its unengineered form, bryostatin comes from the secretions of a sea organism called a bryozoan that attaches to boat hulls, rocky surfaces, and piers. "So, we used bryostatin to wake up the rest of it," added Dang.

Doses of the combination arsenic-bryostatin therapy used in the current research were about 10 percent of the doses administered in typical clinical trials testing both drugs individually. "Arsenic is similar to other chemotherapeutic agents in terms of its potential toxicity, and there's a trade-off in how much harm you do to normal cells versus cancer cells," said Wen-Chien Chou, MD, PhD, lead author of the research. "Yet, the synergistic effects of combining two drugs that activate the same pathway may allow us to avoid toxicity using such low doses."

The researchers will be studying the combination of drugs in additional cell lines and in animal models before clinical trials can be conducted.