Investigating the impact of COX-2 and LOX-5 inhibition on cancer cells irradiated with conventional and hadronic beams

Despite recent advancements in the management of cancer, there is still a large necessity to identify more effective strategies while minimizing undesirable side effects. A promising option is to use hadronic particle beams applied combined with drugs that increase sensitivity to radiation therapy. Moreover, the improved modeling of irradiation-induced DNA damage with Monte Carlo Track Structure (MCTS) codes results from validation with experimentally obtained data. These MCTS codes also provide possibilities for dose determination in treatment planning. The abnormal activation of the cyclooxygenase-2 (COX-2) and/or prostaglandin E2 (PGE2) pathway is commonly observed in various tumor types. This points to the anti-inflammation therapy as a promising cancer treatment option. The activation of the COX-2 pathway decreases the response of tumor cells to radiation therapy while enhancing radiation-induced unwanted late effects in healthy cells. In this regard, COX-2 inhibitors, a structurally diverse class of compounds, can be useful. Also, the increased activity of the 5-LOX signaling pathway in cells exposed to COX-2 inhibitors suggests that dual COX-2 and 5-LOX inhibitors could be the most optimal. In this work, several newly synthesized COX-2 and dual COX-2 and 5-LOX inhibitors were tested on selected cancer cell lines. Based on the results of their cytotoxicity, the most potent inhibitors were selected for combined treatment with radiation. Irradiation with increasing doses of γ-rays was performed at the Laboratory for Molecular Biology and Endocrinology of the Vinča Institute of Nuclear Sciences. Clonogenic assay was done using BxPC-3 (ATCC CRL-1687, pancreatic adenocarcinoma) and HT-29 (ATCC HTB-38, colorectal cancer) cell lines. The obtained survival data was used both for the evaluation of the sensitivity of cells to conventional irradiation and for an investigation of the radiosensitizing potential of tested compounds. The cell geometries were added to the online library of Geant4-DNA, which is openly available to users. To further extend the investigation to irradiation-induced effects on selected cancer models, low-energy protons (≅5 MeV) and alpha-particles (≅ 7.5 MeV) will be used to reproduce the LET values that occur at the mid-SOBP of clinical proton and 12C beams (i.e. around 7 and 75 keV/um, respectively) and will be performed at the 3-MV TANDEM accelerator of the University of Caserta, in Italy. The obtained results will show if the combination of COX-2 and dual COX-2 and 5-LOX inhibitors with radiation of different types has the potential to improve tumor control and whether it can be introduced into clinical routine.