ITMO Scientists Find a Way to Reduce Genomic Instability Tied to Cancer

Genomic instability is a defining feature of cancer that causes cells to accumulate chromosomal rearrangements and mutations, boosts their drug resistance, and reduces the efficacy of treatment. The greater the instability, the more aggressive the tumor. As a result, scientists are seeking ways not only to eliminate cancer cells, but also to reduce their instability.

As their target, ITMO researchers selected a specific molecule linked to cancer: the protein HNRNPA2B1 (hnRNP A2B1) – a reader of m6A modifications, which are chemical labels on RNA molecules that regulate gene activity. When a label and a protein bind, HNRNPA2B1 traps RNA inside the cell, preventing its destruction. In healthy tissues, the process is balanced: they have as much protein as needed to function properly. Cancer cells contain too much protein, and it in turn sustains the RNA molecules that support tumor growth and survival. The scientists found that hesperidin can treat protein without harming healthy tissues.

“We went with hesperidin, a natural compound from the flavonoid class found in the pith of citrus fruits. It’s commonly used to strengthen blood vessels, but it can also function as a radioprotector (reducing DNA damage and rearrangements caused by radiation) and as an antioxidant (combating oxidative stress that destroys cells). We checked whether it can bind to the protein HNRNPA2B1 and change its activity. And the result was positive: hesperidin does interact with the cancer-related protein, and by affecting it, we can mitigate its malignancy,” explains Viacheslav Kravtsov, DSc in biology, a clinical biochemist, and a professor at ITMO’s Infochemistry Scientific Center.

As HNRNPA2B1 is found in various cancers and is associated with radiation resistance, the use of hesperidin may have promising effects in different cancer diseases.

To assess the effect of the compound against glioblastoma, the most aggressive type of cancer, the team used two standard cell lines, U87MG and LN229. These are artificial cells used in cancer research.

A key indicator in such experiments is the state of DNA after radiation. Radiation damages DNA, causing micronuclei – small chromosomal fragments outside a daughter nucleus – to appear in cells. These are caused by division errors or DNA damage. The more micronuclei there are, the greater the instability, the more damage the cell has, and the more aggressively it behaves. Therefore, micronuclei are considered markers of DNA damage.

In the experiment, hesperidin liposomes – microscopic capsules that help the substance enter the cell – are added to glioblastoma cell cultures three hours before radiation. The radiation dose varied from 0 to 8 Gy – the average dose range in radiation therapy. Then, the researchers calculated the number of micronuclei and measured HNRNPA2B1 levels to evaluate tumor aggressiveness and the presence of RNA with m6A modifications. Separately, the team observed what happens with cells during prolonged cultivation and passaging.

“Hesperidin significantly reduced micronuclei formation, both spontaneous and radiation-induced. During prolonged processing, after 25 passages (with transfer into a fresh medium), cells become less aggressive: the frequency of chromosomal rearrangements lowered, while culture looked more ordered outwardly. In other words, cells lost tumor-specific characteristics. A decrease was also observed in HNRNPA2B1 and m6A RNA levels, which means the molecular processes tied to cancer decreased as well,” says Viktoriia Sazonova, the first author of the paper and a Master’s student in infochemistry at ITMO.

The positive effect was also observed in the control group, in which cells received no additional treatment. Hesperidin alone reduced genomic instability and chromosomal abnormalities and therefore suppressed the malignancy of tumor cells.

The researchers plan to patent the hesperidin treatment and are currently considering the use of AI to identify new substances that will affect the protein and help mitigate cancer growth.

Among the ITMO specialists on the team were infochemistry Master’s students Viktoriia Sazonova and Ilia Tonkji, supported by Pavel Zun, an associate professor at ITMO’s Infochemistry Scientific Center and a leader of the biomedical computing research team, and led by professors Viacheslav Kravtsov and Sergey Shityakov. The corresponding paper was co-authored with specialists from the Research Center of Biotechnology RAS.

The study is supported by the Russian Science Foundation (grant No. 22-65-00022П).