Most cancer treatments are effective and end up destroying cancer cells. However, in some cases the cells are able to escape the effects of the therapies. Now, a team of US researchers has discovered how cancer cells avoid death from chemotherapy.
In their laboratory studies, scientists have seen that cancer cells have two ways of escaping drugs designed to starve and kill them.
Most chemotherapies successfully treat cancers and prolong patients’ lives, but they are known not to work in all cases for long, as cancer cells change the process by which they convert fuel into energy (metabolism). ) to counteract the effects of drugs. Many of these drugs are so-called antimetabolics, which alter the cellular processes necessary for the growth and survival of tumors.
The study, which is published in ‘Nature Metabolism‘investigates three drugs (raltitrexed, PALA and brequinar) that block the production of pyrimidines, essential for the synthesis of DNA and RNA in cancer cells. By inhibiting this pathway, the reproduction of cancer cells is interrupted, which can lead to their spontaneous death (apoptosis).
Led by researchers from NYU Langone Health and its Perlmutter Cancer Centerthe work shows how cancer cells survive in a hostile environment due to persistent shortages of the energy from glucose (the chemical term for blood sugar) needed to fuel tumor growth. This better understanding of how cancer cells evade drug attempts to kill them in a low-glucose environment could lead to the design of better or more effective combination therapies.
The researchers discovered that low-glucose tumor microenvironments hinder the consumption of uridine nucleotides, blocking the effectiveness of chemotherapies by preventing the production of DNA and RNA in cancer cells. Additionally, these environments reduce the activation of key proteins (BAX and BAK) that are essential for apoptosis, thereby slowing down cell death of cancer cells.).
The results could lead to the development of new therapies, such as combination chemotherapies, that trick cancer cells
“Our study shows how cancer cells manage to compensate for the impact of low-glucose tumor microenvironments, and how these changes in cancer cell metabolism minimize the effectiveness of chemotherapy,” explains the study’s principal investigator, Minwoo Nam. .
Researchers led by Richard Possemato discovered that low glucose in the tumor microenvironment slows down the consumption of uridine nucleotides, hindering both cancer cell growth and apoptosis (cell death). This finding offers an explanation for how altered metabolism in tumors affects the effectiveness of chemotherapy, making it difficult to destroy cancer cells when they are in a glucose-scarce environment.
The results could lead to the development of new therapies, such as combination chemotherapies, that trick cancer cells into responding as they would in an environment with normal glucose levels. Additionally, the researchers plan to explore how block other metabolic pathways of cancer cells could induce apoptosis in these low glucose environments, which could improve the effectiveness of treatments.
However, more studies are still needed, as some current experimental drugs, such as Chk-1 and ATR inhibitors, are not well tolerated by patients.
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