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Marijuana's Active Ingredient Kills Leukemia Cells

November 2005

The New Drug Study Group in London discovered that Δ9-THC, the active ingredient in
marijuana, works to kill leukemia cells by affecting the gene, MKP3, which may serve as a critical
target for new drugs that are less psychoactive and less controversial.

While leukemia treatment is largely successful, some patients cannot be treated with
conventional therapy; 25 percent of children fail treatment, leaving them with a poor-prognosis
outcome. Scientists have previously reported that Δ9-THC has anti-cancer properties, so its use
as an anti-leukemia drug may be promising, however, the psychoactive side effects, as well as its
current legal status, complicate its use in cancer chemotherapy. Researchers are now trying to
identify the molecular pathways targeted by Δ9-THC in order to develop new drugs that combat
the same disease-pathway without the unwanted side effects.

In a study published in the February 2005 issue of Blood, Dr. Wai Man Liu and colleagues at St.
Bartholomew's Hospital in London reported that Δ9-THC induced cell death in a panel of
leukemia cells, including two AML cell lines. Surprisingly, Dr. Lui's group found that neither CB1
or CB2—the two receptors thought to mediate Δ9-THC effects—were involved in the leukemia
cell death. Activation of the CB1 receptor in the brain produces the psychoactive effects
associated with marijuana use. The CB2 receptor is usually found in cells of the immune system
and may regulate immune function. Moreover, the anti-leukemia properties of Δ9-THC did not
involve the p53 protein, which is often involved in cancer cell death; thus Δ9-THC did not appear
to function through known pathways.

Liu and colleagues used Affymetrix microarrays to investigate the mechanism of cell death
induced by Δ9-THC. In doing so, they found that one gene, MKP3, an inhibitor of the MAPK
pathway, was significantly induced. This was unexpected, but provocative as the MAPK pathway
is thought to be involved in tumor cell survival. Further experiments confirmed that Δ9-THC
inhibited the MAPK pathway in leukemia cells, providing both a mechanism and a potential target
pathway for other anti-leukemia drugs.

Using the Affymetrix Human Genome U133A 2.0 Arrays, the authors could simultaneously detect
changes from more than 18,000 human genes in cells treated with Δ9-THC. This allowed the
team to analyze thousands of genes beyond those previously thought to play a role in leukemia
cell survival and death. The unbiased approach allowed the researchers to identify MKP3 and
unravel the genetic pathways targeted by Δ9-THC.

Liu and his team have begun to uncover the mechanism by which Δ9-THC kills those cells and
potentially promotes longer-term survival. This is a crucial first step towards the much-needed
development of new therapies that can eradicate this deadly disease of affecting millions of
children and adults worldwide.