A well-known drug kills cancer stem cells

A group of Canadian scientists has developed a new method of searching for drugs, the target of which are cancer stem cells. The first successful result of using this method is a well-known drug for the treatment of schizophrenia. It turned out that he could be the killer of cancer. In laboratory experiments, the drug destroys the precursor cells of leukemia cells without harming normal stem cells of the blood. This means that doctors can have a method of treating leukemia, excluding recurrence of the disease.

Despite the fact that surgery, chemotherapy and radiation can rid the body of cancer cells, cancer often returns after months or even years. Today, the culprits of the recurrence of the scientists recognize the so-called cancer stem cells - resistant to chemotherapy and radiation and therefore remain in the body. Theories that stem cells are the source of many cancers have been around for 15 years: in 1997, Canadian scientists first discovered cancer stem cells in certain types of leukemia. Since then, they have been found in breast, brain, lung, gastrointestinal, prostate and ovarian cancers.

According to many scientists, the optimal method of treating these types of cancer would be a combination of traditional anti-cancer drugs with drugs, the target of which are cancer stem cells. But, since there are very few such cells in the body and they are difficult to cultivate in the laboratory, very few such preparations have been found, and none of them is used in clinical practice.

Several years ago, a group of Dr. Mick Bhatia, PhD, from McMaster University collided with several lines of pluripotent stem cells (cells derived from embryos or reprogrammed adult cells that could transform into any type of specialized tissue) , which had some characteristics of cancerous stem cells. The cells of these lines were divided, without being differentiated into more specialized ones.

The purpose of the last work of Dr. Bhatia and his colleagues, recently published in the journal Cell, was to find out whether it is possible, with the help of any chemical compounds, to differentiate or ripen such cells into normal cells, stop abnormally dividing and die a natural death. According to the researchers, this would be a less toxic way of getting rid of cancer stem cells than their direct destruction.

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

One of the most potent compounds was thioridazine (thioridazine), a neuroleptic drug used to treat schizophrenia. Thioridazine blocked the growth of stem cells of acute myeloid leukemia (AML), obtained from patients. In addition, he reduced the number of AML stem cells in mice with leukemia, which developed as a result of the introduction of such cells. In all cases, normal blood stem cells remained healthy. In combination with thioridazine, the standard drug used to treat AML was 55 times more potent against AML stem cells in vitro than with monotherapy with this drug.

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

"Given that this drug is approved and demonstrates such a synergistic effect, we want to immediately move on to trials on patients," says Dr. Bhatia, the scientific director of the Research Institute of Stem Cells and Cancer at McMaster University (McMaster's Stem Cell and Cancer Research Institute).

The search system at the University of McMaster, which identifies the differences between neoplastic and normal human pluripotent stem cells (hPSCs), makes it possible to identify small molecules from the database of known compounds that inhibit the ability of cancer stem cells (CSCs) to self-renew and induce their differentiation. The results already obtained demonstrate the value of neoplastic hPSCs for the identification of drugs targeted by cancer stem cells and allow us to consider the use of differentiation of cancer stem cells as a therapeutic strategy.

A very interesting discovery was made during the research. Thioridazine, whose mechanism of action is based on blockade of receptors of the neurotransmitter dopamine, apparently blocks these receptors on stem cells of leukemia. According to Dr. Bhatia, no one has noticed until now that there are dopamine receptors on cancer stem cells, which are usually associated with the transmission of nerve signals and are found mainly in the brain. But his group found them on the stem cells of not only AML, but also breast cancer. The scientist believes that a test evaluating the amount of dopamine receptors in blood or tissue samples can become an early diagnostic and prognostic marker of these types of cancer.

Colleagues of Dr. Bhatia took his discoveries with a certain amount of justified scientific skepticism. For example, the oncologist Thomas Hudson of the Ontario Institute for Cancer Research would like to know more about the mechanism by which dopamine receptors turn a cell into a cancer stem. And the biologist Piyush Gupta, who studies cancer at the Whitehead Institute for Biomedical Research, USA, and uses a different cellular system when looking for drugs targeting cancer stem cells, believes that pluripotent stem cells can not unequivocally consider imitation of cancer. Nevertheless, he is forced to admit that the results obtained on the model of leukemia are more than convincing.

The next step of Dr. Bhatia's group will be to evaluate the effectiveness of thioridazine in other types of cancer. In addition, the scientists will take a closer look at the capabilities of several drugs identified with thioridazine. In the future, in cooperation with other academic groups and industry, thousands of chemical compounds will be analyzed. According to Dr. Bhatia, the goal of all his partners is to find unique drugs and change the strategy of cancer treatment.

[1], [2], [3], [4], [5], [6]