In aid of chemotherapy
Russian scientists have hacked the protection of cancer cells
Researchers from St. Petersburg and Chernogolovka conducted a study of compounds that suppress the work of heat shock proteins, thanks to which healthy cells experience stress, and the tumor resists drugs. As a result, out of thousands of variants, it was possible to isolate the compound optimal for use in anti-cancer therapy. This is reported by an article published by Oncotarget magazine. The work is supported by an RNF grant.
The operation of any protein or protein complex depends on its spatial configuration, therefore, there are a number of very precise mechanisms for the process of proper folding (folding) of proteins in the cell. Specialized chaperone proteins help many of them to take the right shape. Their work is especially important when the temperature rises or the action of other factors that violate the normal tertiary and quaternary structure (actually three-dimensional convolution) of proteins. Therefore, most chaperones belong to the class of heat shock proteins involved in the stress response of the cell.
Image: RNF Press Service
Cancer cells also use their "regenerating" abilities: activation of chaperones increases their survival rate during various types of antitumor therapy. "It is logical to assume that blocking the chaperone regulation system can lead to an increase in the drug sensitivity of cells," says Irina Guzhova, head of the Laboratory of cell defense Mechanisms at the Institute of Cytology of the Russian Academy of Sciences, one of the leading authors of the work.
The researchers used model HeLa tumor cells containing the bacterial luciferase gene. Under normal conditions, this protein fluoresced (glowed), but temperature stress led to a violation of its spatial structure and the cessation of luminescence. It was resumed only under the action of chaperones, which restored the normal form of luciferase, which allowed scientists to screen more than 1,000 substances-inhibitors (conditionally suppressing the work) of heat shock proteins from the InterBioScreen library created by scientists from the Chernogolovka Moscow region.
Among them, it was possible to identify several molecules that were able to effectively suppress the glow of luciferase, and hence the work of chaperones after a temperature shock, and, consequently, the ability of tumor cells to recover. The authors call the most promising compound CL-43, which inhibited the appearance of heat shock proteins. As a result, Hela-Luc cells became more sensitive to the effects of anticancer drugs such as etoposide, cisplatin and doxorubicin.
CL-43 molecules have not demonstrated toxic effects on the culture of ordinary fibroblast cells. All this, according to scientists, makes the compound a promising new component for the treatment of cancer diseases – including as part of cocktails for chemotherapy. By "punching a hole" in the tumor cells' own defense, the compound will reduce the doses of toxic drugs used in this case.
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