OBJECTIVE: One of the treatments for breast cancer is surgical resection of the tumour and prevention of recurrence with postoperative radiotherapy. Unfortunately, radiotherapy is not always effective enough due to the low sensitivity of cancer cells to ionising radiation. This study aimed to evaluate the radiosensitising properties of resveratrol, piceatannol and polydatin on breast cancer cells, which differ in the presence of hormonal receptors on their surface.
METHODS: The experimental part was carried out on triple-negative breast cancer cells (HCC38) and hormone-dependent cells (MCF7). The study assessed the level of cell death, changes in the expression of genes (BAX, BCL-2) and proteins related to the apoptosis process (CASPASE 3, 8 and P53), changes in the expression of antioxidant enzymes (CATALASE, SOD, GPx1/2) and NRF-2. Additionally, the expression level of RAD51 protein and histone H2AX, which are involved in DNA repair processes, was assessed. Statistical significance was evaluated by a two-way analysis of variance (ANOVA) followed by Tukey\'s post hoc test (p < 0.05).
RESULTS: Ionising radiation in combination with resveratrol or piceatannol activates the apoptosis process by internal and external pathways. Greater sensitivity of MCF7 cells compared to HCC38 cells to ionising radiation in combination with resveratrol is associated with a weaker antioxidant response of cells and reduced intensity of DNA damage repair. DNA repair induced by ionising radiation occurs more effectively in HCC38 cells than in MCF7 cells.
CONCLUSIONS: Resveratrol has the highest radiosensitising potential among the tested stilbene for cells of both lines. The effectiveness of ionizing radiation in combination with resveratrol (to a lesser extent with piceatannol) is more significant in MCF7 than in HCC38 cells.

OBJECTIVE: Radiation therapy is a crucial treatment for nonsmall cell lung cancer (NSCLC), but its effectiveness is limited by the resistance of tumor cells to radiation. This study aimed to evaluate the effect of epicatechin (EC) on radiosensitivity in NSCLC and to determine its relationships with matrix metalloproteinase (MMP)-9.
METHODS: MMP-9 expression was detected by Western blotting, and the expression of the DNA damage marker protein was detected by immunofluorescence. Cell viability was assessed using the CCK-8 assay, and cell proliferation was evaluated using the clonogenesis assay. Flow cytometry was used to determine the cell apoptosis, whereas cell migration and invasion were detected using the transwell assays. The cells were treated with ionizing radiation (IR) and EC to verify the sensitizing effect of EC on radiation therapy.
RESULTS: MMP-9 expression was elevated in the NSCLC cells and tissues. DNA damage and cell apoptosis were increased, whereas cell vigor, proliferation, migration, and invasion were significantly decreased after IR. MMP-9 knockdown strengthened the impact of IR on the biological behaviors of the cells. EC + IR had the best effect on promoting DNA damage and the biological behaviors of the NSCLC cells; alternatively, the overexpression of MMP-9 weakened the role of EC.
CONCLUSIONS: This study shows that EC can downregulate MMP-9 expression, promote DNA damage, reduce cell viability, proliferation, migration, and invasion, and facilitate cell apoptosis, thus, showing potential as a radiosensitizer for NSCLC.

Boron-enhanced proton therapy has recently appeared as a promising approach to increase the efficiency of proton therapy on tumor cells, and this modality can further be improved by the use of boron nanoparticles (B NPs) as local sensitizers to achieve enhanced and targeted therapeutic outcomes. However, the mechanisms of tumor cell elimination under boron-enhanced proton therapy still require clarification. Here, we explore possible molecular mechanisms responsible for the enhancement of therapeutic outcomes under boron NP-enhanced proton therapy. Spherical B NPs with a mode size of 25 nm were prepared by methods of pulsed laser ablation in water, followed by their coating by polyethylene glycol to improve their colloidal stability in buffers. Then, we assessed the efficiency of B NPs as sensitizers of cancer cell killing under irradiation with a 160.5 MeV proton beam. Our experiments showed that the combined effect of B NPs and proton irradiation induces an increased level of superoxide anion radical generation, which leads to the depolarization of mitochondria, a drop in their membrane mitochondrial potential, and the development of apoptosis. A comprehensive gene expression analysis (via RT-PCR) confirmed increased overexpression of 52 genes (out of 87 studied) involved in the cell redox status and oxidative stress, compared to 12 genes in the cells irradiated without B NPs. Other possible mechanisms responsible for the B NPs-induced radiosensitizing effect, including one related to the generation of alpha particles, are discussed. The obtained results give a better insight into the processes involved in the boron-induced enhancement of proton therapy and enable one to optimize parameters of proton therapy in order to maximize therapeutic outcomes.

Radiation resistance is a crucial factor influencing therapeutic outcomes in colorectal cancer (CRC). Baicalein (BE), primarily derived from Scutellaria baicalensis, has demonstrated anti-CRC properties. However, the impact of BE on the radiosensitivity of CRC remains unclear. This study aimed to evaluate the radiosensitization effects of BE and elucidate its mechanism in CRC radiotherapy. We established an in vitro radioresistant cell model (CT26-R) using parental CRC cells (CT26) subjected to ionizing radiation (IR). CT26-R cells were pretreated with or without BE, followed by transfection with pcDNA-NC and pcDNA-JAK2. The proliferation of CT26-R cells treated with BE and IR was assessed using a colony formation assay. A CRC animal model was developed in BALB/c mice via CT26-R cell transplantation. The radiosensitizing effect of BE on CRC was evaluated in vivo. TUNEL assay was conducted to detect apoptosis in tumor tissue. The expression levels of p-STAT3, JAK2, PD-L1, and SOCS3 in vitro and in vivo were measured by western blotting. Our results demonstrated that BE significantly increased radiosensitivity in vitro and in vivo and enhanced apoptosis in tumor tissues. Additionally, BE significantly downregulated the expression of p-STAT3, JAK2, and PD-L1, and significantly upregulated SOCS3 expression. These in vivo effects were reversed by pcDNA-JAK2. In summary, our data suggest that BE enhances CRC radiosensitivity by inhibiting the JAK2/STAT3 pathway.

UNASSIGNED: Naringenin has shown great promise in the realm of cancer therapeutics, demonstrating excellent cytotoxic action toward cancer cells and the enhanced effects of radiation therapy in vitro. However, the medicinal value of naringenin is severely limited clinically by poor bioavailability. Thus, multiple drug-delivery strategies for overcoming this limitation have been developed, of which liposomes are considered the most suitable due to their amphiphilic, modifiable, and biocompatible characteristics. In this study, we investigated the role of naringenin and liposomal-delivered naringenin as adjuncts to radiotherapy in the MDA-MB-231 triple-negative breast cancer cell line in vitro.
UNASSIGNED: Liposomal-naringenin was synthesized by thin-film hydration and extrusion and was characterized by spectrophotometry, dynamic light scattering, and zeta potential. The effects of free-from naringenin and liposomal-naringenin were evaluated toward MDA-MB-231 cell viability when combined with varying doses of radiation. Additionally, cell growth patterns, morphology, and colony formation were evaluated.
UNASSIGNED: The analysis demonstrated IC50 values of 387.5 and 546.6 µg/ml for naringenin and liposomal-naringenin, respectively. Naringenin and liposomal-naringenin significantly lowered cell viability, proliferation, and colony formation dose-dependently, as compared to radiation in isolation.
UNASSIGNED: The findings presented herein concur with previous accounts of the radiosensitizing potential of naringenin and further highlight the considerable biomedical application of liposomal-naringenin within the realm of radiotherapy.

Despite active clinical trials on the use of Oleandrin alone or in combination with other drugs for the treatment of solid tumors, the potential synergistic effect of Oleandrin with radiotherapy remains unknown. This study reveals a new mechanism by which Oleandrin targets ATM and ATR kinase-mediated radiosensitization in lung cancer. Various assays, including clonogenic, Comet, immunofluorescence staining, apoptosis and Cell cycle assays, were conducted to evaluate the impact of oleandrin on radiation-induced double-strand break repair and cell cycle distribution. Western blot analysis was utilized to investigate alterations in signal transduction pathways related to double-strand break repair. The efficacy and toxicity of the combined therapy were assessed in a preclinical xenotransplantation model. Functionally, Oleandrin weakens the DNA damage repair ability and enhances the radiation sensitivity of lung cells. Mechanistically, Oleandrin inhibits ATM and ATR kinase activities, blocking the transmission of ATM-CHK2 and ATR-CHK1 cell cycle checkpoint signaling axes. This accelerates the passage of tumor cells through the G2 phase after radiotherapy, substantially facilitating the rapid entry of large numbers of inadequately repaired cells into mitosis and ultimately triggering mitotic catastrophe. The combined treatment of Oleandrin and radiotherapy demonstrated superior inhibition of tumor proliferation compared to either treatment alone. Our findings highlight Oleandrin as a novel and effective inhibitor of ATM and ATR kinase, offering new possibilities for the development of clinical radiosensitizing adjuvants.

Radiotherapy is an invaluable tool in the treatment of cancer. However, when used as a monotherapy, it fails to provide curative outcomes. Chemotherapy drugs are often included to boost the effects of radiation. Key classes of radiosensitizing drugs include platinum compounds, anthracyclines, antimetabolites, taxanes, topoisomerase inhibitors, alkylating agents, and DNA damage repair inhibitors. Chemoradiotherapy suffers from not only systemic toxicities from chemotherapy drugs but also synergistic radiation toxicity as well. It is critical to deliver radiosensitizing molecules to tumor cells while avoiding adjacent healthy tissues. Currently, nanomedicine provides an avenue for tumor specific delivery of radiosensitizers. Nanoscale delivery vehicles can be synthesized from lipids, polymers, or inorganic materials. Additionally, nanomedicine encompasses stimuli responsive particles including prodrug formulation for tumor specific activation. Clinically, nanomedicine and radiotherapy are intertwined with approved formulation including DOXIL and Abraxane. Though many challenges remain, the ongoing progress evidences a promising future for both nanomedicine and chemoradiotherapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

UNASSIGNED: A patient with widespread intensely prostate-specific membrane antigen-expressing, BRCA gene mutation-positive bone metastases at the time of prostate cancer diagnosis had progressed on multiple lines of standard therapy. He received 177 Lu-prostate-specific membrane antigen 8.5 GBq augmented by a short course of olaparib radiosensitization and achieved 90% decrease in serum PSA level after a single treatment. His tumor response was much better than expected by predictive dosimetry. However, his marrow radiotoxicity was worse than anticipated and required hospitalization. This suggests radiosensitizing agents to be a double-edged sword that must be carefully considered and balanced during activity prescription.

OBJECTIVE: Despite the established antitumor effectiveness and synergistic interactions of melatonin with photon irradiation, its role in carbon-ion radiotherapy remains uncertain. This study aimed to elucidate the mechanisms and potential clinical advantages of combining exogenous melatonin therapy with carbon-ion radiotherapy.
METHODS: The investigation assessed the impact of combining exogenous melatonin with photon or carbon-ion irradiation on cell-cycle modulation and DNA-repair capability using the melanoma cell line B16F10. RNA sequencing and bioinformatics analysis were conducted to explore mechanisms and evaluate potential clinical benefits, with validation performed on the osteosarcoma cell line LM8.
RESULTS: Pre-treatment with melatonin reduced the survival fraction of B16F10 and LM8 cells upon exposure to photon and carbon-ion radiation. Mechanistically, melatonin was found to inhibit G2/M arrest, preserve DNA damage, and suppress key genes involved in DNA double-strand break repair after 8 Gy carbon-ion radiation. Furthermore, RNA sequencing and bioinformatics analysis revealed favorable changes in genes associated with survival and metastasis, highlighting potential clinical significance. LM8 cells treated with melatonin exhibited increased radiosensitivity and suppression of DNA-repair proteins.
CONCLUSIONS: The combination of exogenous melatonin not only heightened radiosensitivity and modulated hallmark tumor gene sets in vitro but also markedly suppressed the efficiency of DNA double-strand break-repair pathway, thus enhancing the cytotoxicity of carbon-ion radiotherapy.

OBJECTIVE: Acetyl glucose adducts (UTX-114, -115, and -116) were prepared from gefitinib, and their characteristics (e.g., anticancer activity, structural property) were analyzed.
METHODS: Cytotoxicity and radiosensitizing properties of the UTX-114 family were examined using A431 cells. Supramolecular associations between the UTX-114 family compounds and the tyrosine kinase domain of epidermal growth factor receptor (EGFR-tyk) were also examined. The interactive analyses of the UTX-114 family compounds with EGFR-tyk were performed using docking simulation technique.
RESULTS: The UTX-114 family showed a similar cytotoxicity as gefitinib, yielding IC50 values of 31.2 μM (gefitinib), 34.3 μM (UTX-114), 36.8 μM (UTX-115), and 39.4 μM (UTX-116). The EGFR-tyk inhibition ratios (IR) of UTX-114, -115, and -116 to gefitinib were 1.515, 0.983, and 0.551, respectively. The EGFR-tyk inhibitory activity of UTX-114 was higher than that of gefitinib. UTX-114 also showed the highest radiosensitizing activity among the tested compounds. UTX-114 expressed 1841 conformers (-8.989~15.718 kcal/mol) with the solvation free energy (dGW) of UTX-114 decreasing with increasing conformational energy, ranging between -354.955~ -260.815 kJ/mol. Interactive energies of gefitinib, UTX-114, -115, and -116 with EGFR-tyk were -123.640, -144.053, -120.830, and -124.658 kcal/mol, respectively.
CONCLUSIONS: UTX-114 yielded the lowest interaction energy with EGFR-tyk among tested compounds. Given the association behavior between UTX-114 and EGFR-tyk, along with its other observed properties, UTX-114 appears to be a viable therapeutic possibility.