Johns Hopkins
Kimmel Cancer Center scientists have discovered why
arsenic has long been a successful way to treat certain
leukemias and, in the process, have shown that a
combination of the poison and a second naturally occurring
toxin may provide a potent new therapy for them.
The researchers discovered that arsenic, a naturally
occurring element, actually activates the same cellular
self-destruct mechanism as a compound called bryostatin, a
toxin found in coral-like aquatic organisms. The findings
are reported in the March 16 issue of 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, or APL, a
cancer of the blood and bone marrow characterized by
unhealthy myeloid or white blood cells.
The method in which arsenic kills cancer cells,
however, was not fully understood until Johns Hopkins
scientists used molecular studies to track the poison's
target to NADPH oxidase, an oxygen-producing enzyme
complex.
In their experiments, the researchers used a low-dose
combination of bryostatin and arsenic to kill APL cell
lines in the laboratory.
"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, vice dean
for research and professor of
medicine,
cell biology,
pathology and
oncology at the School of Medicine. "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 arsenic alone is not enough, the researchers said.
"Even with arsenic treatment, much of the NADPH oxidase
remains dormant in our system," Dang said. Previous
molecular studies, however, showed that NADPH oxidase also
is activated by the drug 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," Dang said.
Doses of the combination arsenic-bryostatin therapy
used in the Johns Hopkins research were one-tenth 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, a
postdoctoral student at Johns Hopkins and first 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
these drugs in additional cell lines and must test the
strategy in animal models before clinical trials in APL 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," Dang said.
APL is a subtype of acute myeloid leukemia, which is
the most common form of adult leukemia.
The research was funded by the National Cancer
Institute of the National Institutes of Health. Other
participants in this research were Wen-Chien Chou, Chunfa
Jie, Andrew Kenedy, Richard Jones and Michael Trush.
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