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Drug from alcoholism restrained the growth of cancer cells

Breast Cancer Cells MDA-MB-231
Shuai Dong / Wikimedia Commons

The drug disulfiram, which is usually prescribed for the treatment of alcoholism, helps to contain the growth of cancerous tumors. Its metabolite inhibits the degradation of intracellular proteins by inhibiting the enzyme p97. The molecular action of the drug on cancer cells is reported by scientists from the Czech Republic and four other countries in the world,  published  in the journal Nature .

The mechanism of suppressing the growth of cancer cells has not yet been fully understood, but sometimes scientists notice anticancer effects in drugs that have been developed for other purposes. Disulfiram (DSF) is used to treat alcoholism, but scientists have already reported on its anticancer action in preclinical studies, and one of the metabolic products of DSF (DTC, diethyldithiocarbamate) has already been used in clinical trials as a remedy for breast cancer. To ensure the effectiveness of DSF as a means to contain the growth of cancer cells and to understand how it works at the molecular level, Jiri Bartek of Palacký University and colleagues from the Czech Republic, Sweden, Switzerland, the United States and China conducted a number of laboratory studies .

First they conducted epidemiological analysis on the basis of data from the Danish national demographic and medical registries. Scientists selected patients with cancer who received DSF prior to diagnosis, but then discontinued (former users), those who took DSF both before and after the diagnosis (regular users), and those who did not receive DSF at all. For all categories, the risk factor for cancer mortality was calculated.

Cancer mortality was higher among former users of the drug than among patients who did not take DSF at all. This is expected, since alcoholism is considered a risk factor. Also, scientists noticed that in regular users of DSF, the lethal outcomes provoked by cancer were fewer in all cases in aggregate, and separately for cases of colon cancer, prostate and breast cancer. This trend has persisted even among patients who have already developed metastases.

Then the scientists decided to confirm in mice that the anti-cancer properties of DSF depend on copper. To do this, the mice were injected with cancer cells and divided into groups with a normal diet without additives, the second group also received copper gluconate (CuGlu), the third group added DSF to the diet, and the fourth group received both DSF and copper gluconate. Scientists have measured the size of the tumor in response to a diet. 

Different combinations of DSF and copper in different ways inhibited the growth rate of the tumor, but the best results were found in the group DSF and DSF / CuGlu, where the suppression was 57 and 77 percent, respectively. The difference between these groups was also significant (P = 0.0038).

From here scientists deduced the hypothesis that the DTC-copper complex (CuET) is an important component in the fight against cancer. Using mass spectroscopy, they measured the content of CuET in mouse tissue samples and found a large number in samples taken from tumors, with slightly more in the DSF / CuGlu group than in the DSF group. Further molecular analysis made it possible to establish that the complex CuET suppresses tumor growth by inhibiting the degradation of the protein, which is provoked by the enzyme  p97 . CuET inhibits p97 by binding to its “helper”, the NPL4 protein. 

Thus, the scientists compiled a model by which the DSF suppresses the growth of cancer cells. According to this model, DSF decomposes to the DTC-copper complex, which accumulates in tumors, binds NPL4 and inhibits the action of the enzyme p97. The authors believe that the metabolite that they discovered is the main anticancer agent, as it is enhanced by contact with copper. These results confirm some of the available data. For example, scientists have already suggested treating myeloma with inhibition of p97. 

This is not the first time that the anti-cancer effect has been found in drugs intended for the treatment of other diseases: it has already been found in diclofenac, and even found in an industrial substance that prevents corrosion. In addition, scientists developed a universal anti-cancer vaccine, and successfully  tested it in three patients with melanoma.

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