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.