A well-known drug for treating schizophrenia may be a cancer killer, too. In lab studies, the drug wiped out a precursor to leukemia cells without harming normal cells. That means it could give doctors a long-sought way to eliminate every trace of leukemia in patients so that the cancer can never come back.
Even though surgery, chemotherapy, and radiation can get rid of a tumor or leukemia cells, the cancer often returns months or years later. One culprit may be so-called cancer stem cells, which give rise to cancer cells. These stem cells resist chemotherapy and radiation, and linger in the body. Some researchers think that combining conventional cancer drugs with a drug that targets cancer stem cells may be the best way to vanquish certain cancers. But because these cancer stem cells are scarce and hard to grow in the lab, few such drugs have been identified and none are in clinical use.
Now, a Canadian team has found a new way to test for drugs that target cancer stem cells. They used human pluripotent stem cells, which are cells made from embryos or reprogrammed adult cells that have the ability to develop into different tissue types. A few years ago, stem cell researcher Mickie Bhatia's team at McMaster University in Hamilton, Canada, stumbled across several pluripotent stem cell lines that share some characteristics of cancer stem cells: The cells keep dividing and won't develop, or differentiate, into more specialized cells.
In its new work, Bhatia's group tested whether various chemical compounds could coax the cells to differentiate, or mature, into normal cells so they would stop dividing abnormally and die a natural death. The researchers hoped this might be a less toxic way to get rid of the cancer stem cells than by killing the cells directly.
After screening hundreds of compounds including approved drugs, the researchers found a few that did what they wanted: The chemicals caused the cancer-like stem cells to differentiate without harming normal, healthy stem cells needed by the body. One of the most potent compounds was thioridazine, an antipsychotic drug used to treat schizophrenia. The drug also blocked the growth of acute myeloid leukemia (AML) stem cells taken from patients. And it knocked down the number of AML stem cells in mice injected with these cells that developed leukemia—but it spared normal blood stem cells.
When combined with thioridazine, the standard drug used to treat AML was 55 times more potent at killing AML cells in a lab dish than it was alone, Bhatia and colleagues report today in Cell. The team is now planning a clinical trial to test the drug combo in 15 AML patients who are no longer responding to the standard drug alone. "Our feeling is, given that it's approved and has this synergistic effect, we want to go straight into patients," Bhatia says.
The study also revealed a curious finding. Thioridazine, which blocks receptors for the neurotransmitter known as dopamine, appears to also work on leukemia stem cells by blocking these receptors. Bhatia says that until now, nobody had noticed that cancer stem cells have dopamine receptors, which are normally associated with neural signaling and found mainly in the brain. But his group also found them in breast cancer stem cells. He suggests that a test that measures the quantity of dopamine receptors in blood or tissue samples could detect cancer or predict a patient's prognosis.
Cancer biologist Piyush Gupta of the Whitehead Institute in Cambridge, Massachusetts, who has used a different cell system to find drugs that target cancer stem cells, says he would not necessarily expect the pluripotent stem cell system to mimic cancer. But "the relevance is shown compellingly by the authors in the context of a leukemia cancer model."
He and others say they're glad to see a new technique for identifying drugs that work against cancer stem cells. But cancer researcher Thomas Hudson of the Ontario Institute for Cancer Research in Canada says he'd like to know more about the mechanism by which dopamine receptors make a cell a cancer stem cell.