In lab experiments, Canadian researchers found that thioridazine can alter cancer stem cells that give rise to a type of leukemia, as well as those that generate certain breast cancer cells, without harming normal stem cells.
The discovery, reported Thursday in the journal Cell, came after researchers screened about 3,000 compounds in search of those that would selectively inhibit human cancer stem cells.
Thioridazine is one of about 20 agents winnowed down through high-tech drug screening that appear to work against cancer stem cells, said principal investigator Mick Bhatia, scientific director of the Stem Cell and Cancer Research Institute at McMaster University.
"Cancer stem cells, what they do is they keep proliferating," Bhatia said from Hamilton. "But they don't do what normal stem cells do, which is make other cell types. And then those cells perform their function and then die. That's the normal life cycle.
"Cancer stem cells refuse to go through that life cycle because they never differentiate. They just keep making copies of themselves."
That's why, even if a patient's malignancy appears to have been eradicated with chemotherapy and radiation, the cancer can come back, Bhatia said.
"And the feeling there is that the drugs we're using aren't targeting the cancer stem cells, so you're not getting to the root. You're just picking the dandelion off the top.
"And it looks good for a while, the lawn looks fine, but if you don't dig at it and get the root, it just comes back."
Bhatia admits that thioridazine's apparent power over cancer stem cells came as a bit of a surprise.
The drug works against schizophrenia, for example, by targeting dopamine receptors in the brain. Dopamine is a chemical messenger that plays a variety of roles in the brain, including helping to regulate attention, cognition and movement.
The drug is also used to treat the symptoms of Parkinson's disease, which develop in response to declining dopamine levels caused by the death of brain cells that make the neurotransmitter.
Thioridazine doesn't appear to kill cancer stem cells, but rather encourages them to differentiate, thus exhausting the pool of self-renewing cells.
The researchers showed that the drug affects leukemia stem cells without harming normal blood stem cells. It turns out that unlike normal blood stems cells, leukemia cells have a dopamine receptor on their surfaces — making them vulnerable to the drug.
Dopamine receptors also appear on some breast cancer stem cells, the researchers found.
"This gives us some explanation," Bhatia said. It also suggests that dopamine receptors might serve as a biomarker for early detection of rare, tumour-initiating cells in patients.
Michael Rudnicki, CEO and scientific director of the Stem Cell Network of Canada, described the paper as a "beautiful study, a very nice piece of work."
"I think this paper really exemplifies the Canadian leadership in cancer stem cell research," Rudnicki said Thursday from Ottawa. "Cancer stem cells were really discovered here in Canada, and this work takes it to a new level."
He said the researchers' findings strongly support the notion that already-approved, "human-ready" drugs exist in the global pharmaceutical armamentarium that could bolster doctors' ability to defeat some cancers.
"Everything that we can do to build up the toolbox for the clinicians treating cancer will help this," said Rudnicki, who was not involved in the study.
The McMaster-led team, which includes physicians, is planning to test thioridazine in combination with standard anti-cancer drugs in a small group of adults with acute myeloid leukemia who have not responded to chemotherapy alone.
The researchers' next step is to investigate the effectiveness of thioridazine in other types of cancer, as well as exploring the potential of the other compounds identified so far, Bhatia said.
"We really want these drugs to be something that we can target at a clinical level."
In the future, thousands of other compounds will be analyzed with McMaster's robotic stem cell screening system in collaboration with other academic groups and the pharmaceutical industry.
"The goal for all of the partners," said Bhatia, "is the same — to find unique drugs to change the way we tackle and treat cancer."