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Tumors and their defense mechanisms against anti-cancer therapies. ~ Dr. Antonio Giordano (SHRO)

Updated: Jun 23, 2023

Radiotherapy and chemotherapy treatments used in cancer care act on DNA, inducing single and double-strand breaks. Cells possess numerous repair mechanisms, but double-strand breaks are the most toxic to cells. There are two mechanisms for repairing double helix DNA breaks, one conservative and one non-conservative for genetic information.

However, some tumor cells have a DNA repair mechanism that is so efficient that it reduces the efficacy of radiotherapy and chemotherapy treatments. It is worth noting that many treatments used in oncology therapy produce double-strand breaks in DNA, activating repair mechanisms.

About half of the patients diagnosed with hepatocellular carcinoma produce an RNA molecule called NIHCOLE, present in more aggressive tumors, where the prognosis is unfavorable. Eliminating NIHCOLE RNA molecules make tumor cells more susceptible to death when treated with radiotherapy or chemotherapy.

In a study reported by Cell Reports, it was observed that the NIHCOLE molecule forms a bridge capable of binding together the broken pieces of DNA, interacting with proteins that recognize fragmented DNA. The discovery and intuition that links the NIHCOLE RNA molecule to these proteins could represent an important strategy for the treatment of the most aggressive liver tumors.

To understand how these mechanisms work, nanotechnology was used and the group led by scientist Fernando Moreno-Herrero employed techniques that allow for a closer study of these processes, in order to create "a class of NIHCOLE inhibitors" drugs that could be effective in cases of liver tumors with unfavorable prognosis.

Using magnetic tweezers and attaching a tiny magnetic bead to one end of the DNA to be repaired, the cells attach and repair the damaged DNA. Basically, NICHOLE confers an advantage to cells, thereby supporting "the malignant proliferation of tumor cells."

This is possible because the repair mechanism modulated by NIHCOLE is non-conservative and introduces errors in the sequence of repaired DNA, thereby increasing the possibility of new mutations. Recently discovered RNA molecules like NIHCOLE have a "prevalent function in cancer," which is why it is necessary to study their mechanisms and create "inhibitor" drugs that do not interfere with anti-cancer treatments.

Recently, a scientific paper by Luigi Alfano et colleagues was published in the international journal 'Nucleic Acid Research' in which the authors described the role of a protein called AUF-1 in regulating the formation of DNA/RNA hybrids in repairing double-strand DNA breaks. It was shown that their presence inhibits conservative repair, increasing genome instability, which is a mechanism underlying neoplastic transformation.

With the evidence that NIHCOLE is important in promoting DNA repair, and determining a particularly aggressive malignant proliferation, this capacity for DNA repair could be targeted to prevent and defeat cancer.

Professor Antonio Giordano, M.D. Ph.D., is the Founder & Director of Sbarro Institute situated at Temple University's College of Science and Technology, Philadelphia, USA.

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