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Mathematical modelling of enhanced radiotherapy effectiveness by blocking antioxidant defiance system of cancer cells in personalized therapyтезисы доклада
- Авторы: Golyshev G., Goltsov A.
- Сборник: Сборник материалов российско-швейцарского семинара «Инновационные технологии для разработки медицинского оборудования и новых лекарств»
- Тезисы
- Год издания: 2023
- Издательство: МИРЭА-Российский технологический университет
- Местоположение издательства: Москва
- Первая страница: 15
- Последняя страница: 16
- Аннотация: The significant progress in radiotherapy (RT) in the past decades has been made due to the implementation of the novel radiotherapy equipment with high-quality ionizing beams, development of the precision methods of dose delivery, and the use of personalized RT treatment plans. However, there remains a problem of high variability in the responses of individual patients to RT. To gain further therapeutic benefit of RT, the combination of RT with drug targeted therapy is considered as the promising way to enhance tumour response in patients to RT. Combination RT with targeted therapy gives a synergetic effect in the cancer treatment due to drug inhibition of key metabolic and signaling pathways activated in cancer cells bearing a different set of oncomutations. In this work, we developed a computational method in systems radiobiology to investigate effectiveness of RT in combination with targeted therapy which directs at the inhibition of NRF2 antioxidant system of cancer cells (AOS). NRF2 transcriptional factor is a key element of the defensive cellular system which is activated under oxidative stress in cells induced in part by ionizing radiation. Its activation triggered by the increasing reactive oxygen species (ROS) in the cells leads to the expression of a large number of antioxidant enzymes which neutralize ROS. We assumed that suppression of the NRF2 AOS in cancer cells enhances the sensitivity of the cells to RT due to the increasing damage of cancer cell DNA by ROS generated by water radiolysis. In the course of this project, a joint mathematical model of RT and the NRF2 AOS was developed in order to investigate molecular mechanisms of radioresistance and radiosensitivity of cancer tumors at the activation and inhibition of the NRF2 AOS. The model describes the following processes in cancer cells under ionizing radiation (IR): 1) tumor growth, 2) inhibition of cancer cell growth due to the direct and indirect actions of IR, 3) generation of ROS, and 4) activation and drug inhibition of the NRF2 antioxidant system. The model was validated on the experimental data on the radiation action (2x5 Gy) on growth inhibition of the squamous cell line of skin cancer HSC-4 at normal and inhibited function of the NRF2 antioxidant system. The results of the modelling showed that the in silico model satisfactorily described the increasing damaging effect of RT when suppressing the NRF2 antioxidant system of cancer cells. The developed model of the molecular mechanism underlying enhancing sensitivity of cancer cells to RT can be used in the development of the new strategy to sensitize tumour to RT in cancer patients by combined action of radiotherapy with drug targeted the NRF2 antioxidant defense system of cancer cells.
- Добавил в систему: Гольцов Алексей Николаевич