Study examines effects of chemotherapy on the mechanical properties of prostate cancer cells

Malignant tumor cells deform mechanically more easily than normal cells and can thus migrate through the body. The mechanical properties of prostate cancer cells treated with the most widely used cancer drugs were studied at the Institute of Nuclear Physics of the Polish Academy of Sciences in Kraków. According to the researchers, current drugs can be used more effectively and in lower doses.

In cancer, the ability of neoplastic cells to mechanically deform is a key factor that contributes to metastasis. At the Institute for Nuclear Physics of the Polish Academy of Sciences (IFJ PAN) in Kraków, research has been carried out on the mechanical properties of cells for a quarter of a century.

The latest study, carried out in collaboration with the Department of Medical Biochemistry at Jagiellonian University Medical College, looked at several drugs currently used in prostate cancer chemotherapy, and specifically, their effects on the mechanical properties of cancer cells. The results are optimistic: everything indicates that the doses of some drugs can be reduced without the risk of reducing their effectiveness.

Chemotherapy is an extremely brutal attack not just on the patient’s cancer cells, but on all cells in the body. By using it, doctors hope that the more sensitive tumor cells will die before the healthy ones begin to die. In this situation, it is important to know how to choose the optimal drug in a given case and how to determine its minimum dose, which, on the one hand, guarantees the effectiveness of the treatment and, on the other hand, minimizes the adverse effects of the therapy.

Physicists at IFJ PAN showed in 1999 that cancer cells deform mechanically more easily. In practice, this means that they can squeeze their way through the narrow vessels of the circulatory and / or lymphatic system more efficiently.

The mechanical properties of a cell are determined by elements of its cytoskeleton such as the microtubules we examined, which consist of tubulin (a protein), actin filaments and intermediate filaments of proteins such as keratin or vimentin. Biomechanical measurements of cells are carried out with an atomic force microscope. Depending on our needs, we can press the probe more or less onto the cell and thus receive a mechanical response from structures that are either on their surface, i.e. on the cell membrane, or deeper, even on the cell nucleus. However, to get information about the effects of a drug, we need to assess the contribution each type of cytoskeletal fiber makes to the mechanical properties of the cell. “

Malgorzata Lekka, professor, Department of Biophysical Microstructures, Institute of Nuclear Physics of the Polish Academy of Sciences

In the results currently reported, the Krakow-based physicists presented experiments using the commercially available human prostate cancer cell line DU145. This line was chosen for its drug resistance. With long-term drug exposure, these cells become resistant to the drugs over time and not only do not die, but even begin to divide.

“We focused on the effects of three commonly used drugs: vinflunine, colchicine and docetaxel. They all act on the microtubules, which is desirable because these fibers are essential for cell division. Docetaxel stabilizes the microtubules and therefore increases their stiffness of the tumor The other two drugs destabilize the microtubules so that cancer cells can migrate. However, due to the impaired functions of the cytoskeleton, they cannot divide, “says doctoral student Andrzej Kubiak. the first author of the article published in the prestigious Nanoscale.

The Krakow researchers analyzed the viability and mechanical properties of the cells 24, 48 and 72 hours after drug treatment and found that the largest changes were observed three days after drug exposure. This enabled them to determine two concentrations of drugs: a higher one that destroyed cells and a lower one that, although the cells survived, were found to have altered their mechanical properties.

For obvious reasons, what happened to the cells in the latter case was of particular interest. The accurate interpretation of some of the results required several tools, such as a confocal microscope and flow cytometry. Their use was possible thanks to the collaboration with the Institute of Pharmacology of the Polish Academy of Sciences in Kraków, the Department of Cell Biology at the Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University and the University of Milan (Department of Physics, University) degli Studi di Milano).

“It has been known for some time that when microtubules are damaged, actin filaments take over some of their functions. Combining measurements of the mechanical properties of cells with images from confocal and fluorescence microscopes allowed us to observe this effect Determine exactly the areas in the cell affected by a certain drug and understand how its effects change over time, “emphasizes doctoral student Kubiak.

Practical conclusions can be drawn from the research of the Kraków physicists. For example, the effect of vinflunine is clearly visible in the core area, but is compensated for by the actin filaments. As a result, the cell remains rigid enough to continue to multiply. On the other hand, the effects of docetaxel are most visible 48 hours after drug administration, mainly on the cell periphery. This fact also makes us aware of the increasing role of actin filaments and means that therapy should be supported with a drug that acts on these filaments.

“So far, little research has been done into the effectiveness of low concentrations of anti-cancer drugs. We show that this is a really worthwhile topic. Understanding the mechanisms of action of individual drugs allows us to maintain:” and sometimes even increase – their current one Effectiveness while reducing the side effects of chemotherapy. This makes chemotherapy more patient-friendly, which should not only affect the patient’s physical health, but also the psychological attitude required in the fight against cancer “, concludes Prof. Lekka.

Source:

The Henryk Niewodniczanski Institute of Nuclear Physics Polish Academy of Sciences

Journal reference:

Kubiak, A. et al. (2021) Stiffening of DU145 prostate cancer cells propelled by actin filaments – microtubule crosstalk that confers resistance to microtubule targeting drugs. Nanoscale. doi.org/10.1039/D0NR06464E.

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