Well-known drug kills cancer stem cells

A group of Canadian scientists have developed a new method for finding drugs that target cancer stem cells. The first successful result of this method is a well-known drug for treating schizophrenia. It turns out that it can also be a cancer killer. In laboratory experiments, the drug destroys leukemia precursor cells without harming normal blood stem cells. This means that doctors may have a method for treating leukemia that eliminates relapses of the disease.

Although surgery, chemotherapy, and radiation can rid the body of tumor cells, cancer often returns months or even years later. Today, scientists believe that the culprits of relapses are so-called cancer stem cells – resistant to chemotherapy and radiation and therefore remaining in the body. The theory that stem cells are the source of many types of cancer is already 15 years old: in 1997, Canadian scientists first identified cancer stem cells in some types of leukemia. Since then, they have been found in breast, brain, lung, gastrointestinal, prostate, and ovarian cancers.

Many scientists believe that the optimal treatment for these types of cancer would be to combine traditional anticancer drugs with drugs that target cancer stem cells. But because these cells are so rare in the body and difficult to culture in the lab, very few such drugs have been found, and none are used in clinical practice.

Several years ago, the group of Dr. Mick Bhatia, PhD, of McMaster University encountered several lines of pluripotent stem cells (cells derived from embryos or reprogrammed adult cells that can transform into any type of specialized tissue) that had some characteristics of cancer stem cells. The cells in these lines were dividing without differentiating into more specialized cells.

The goal of Dr. Bhatia and his colleagues' latest work, recently published in the journal Cell, was to see if chemicals could be used to induce these cells to differentiate, or mature, into normal cells, stop dividing abnormally, and die a natural death. This, the researchers believe, would be a less toxic way of getting rid of cancer stem cells than killing them outright.

After screening hundreds of compounds, including already approved drugs, the researchers identified several that fit their requirements: These chemicals caused pluripotent stem cells to differentiate without harming the normal stem cells needed by the body.

One of the most potent compounds was thioridazine, an antipsychotic drug used to treat schizophrenia. Thioridazine also blocked the growth of acute myeloid leukemia (AML) stem cells obtained from patients. It also reduced the number of AML stem cells in mice with leukemia that developed as a result of the injection of such cells. In all cases, normal blood stem cells remained healthy. When combined with thioridazine, the standard drug used to treat AML showed 55 times greater activity against AML stem cells in vitro than when the drug was used alone.

Scientists plan to conduct clinical trials of this combination on 15 patients with AML resistant to monotherapy with a standard drug.

"Given that this drug is approved and shows such a synergistic effect, we want to move straight into patient trials," said Dr. Bhatia, scientific director of McMaster's Stem Cell and Cancer Research Institute.

A search engine developed at McMaster University that differentiates between neoplastic and normal human pluripotent stem cells (hPSCs) has identified small molecules from a database of known compounds that inhibit the self-renewal capacity of cancer stem cells (CSCs) and induce their differentiation. The results already obtained demonstrate the value of neoplastic hPSCs for identifying drugs that target cancer stem cells and allow us to consider exploiting cancer stem cell differentiation as a therapeutic strategy.

The study made a very interesting discovery. Thioridazine, which works by blocking receptors for the neurotransmitter dopamine, appears to block these receptors on leukemia stem cells as well. According to Dr. Bhatia, no one had noticed that cancer stem cells had dopamine receptors, which are usually associated with the transmission of nerve signals and are found mainly in the brain. But his team found them on stem cells not only from AML, but also from breast cancer. The scientist believes that a test that evaluates the amount of dopamine receptors in blood or tissue samples could become an early diagnostic and prognostic marker for these types of cancer.

Dr. Bhatia’s colleagues have treated his findings with a certain amount of justified scientific skepticism. For example, oncologist Thomas Hudson of the Ontario Institute for Cancer Research would like to know more about the mechanism by which dopamine receptors transform a cell into a cancer stem cell. And biologist Piyush Gupta, who studies cancer at the Whitehead Institute for Biomedical Research in the United States and uses a different cell system to search for drugs targeting cancer stem cells, believes that pluripotent stem cells cannot be considered an imitation of cancer. Nevertheless, he has to admit that the results obtained in the leukemia model are more than convincing.

The next step for Dr. Bhatia’s team will be to evaluate thioridazine’s effectiveness in other types of cancer. They will also look more closely at the capabilities of several drugs identified along with thioridazine. In the future, thousands of compounds will be analyzed in collaboration with other academic groups and industry. The goal of all of his partners, Dr. Bhatia says, is to find unique drugs and change the strategy of cancer treatment.

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