Radiosensitizing effect of a novel CTSS inhibitor by enhancing BRCA1 protein stability in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) patients harboring wild-type breast cancer susceptibility gene 1 (BRCA1) account for most TNBC patients but lack adequate targeted therapeutic options. Although radiotherapy (RT) is the primary treatment modality for TNBC patients, radioresistance is one of the major challenges. RT-induced increase in cathepsin S (CTSS) causes radioresistance through suppressing BRCA1-mediated apoptosis of tumor cells, which was induced by CTSS-mediated degradation of BRCA1. Targeting CTSS may provide a novel therapeutic opportunity for TNBC patients. Publicly available data and human tissue microarray slides were analyzed to investigate the relationship between CTSS and BRCA1 in breast cancer patients. A CTSS enzyme assay and in silico docking analysis were conducted to identify a novel CTSS inhibitor. RO5461111 was used first to confirm the concept of targeting CTSS for radiosensitizing effects. The MDA-MB-231 TNBC cell line was used for in vitro and in vivo assays. Western blotting, promoter assay, cell death assay, clonogenic survival assay, and immunohistochemistry staining were conducted to evaluate novel CTSS inhibitors. CTSS inhibitors were further evaluated for their additional benefit of inhibiting cell migration. A novel CTSS inhibitor, TS-24, increased BRCA1 protein levels and showed radiosensitization in TNBC cells with wild-type BRCA1 and in vivo in a TNBC xenograft mouse model. These effects were attributed by BRCA1-mediated apoptosis facilitated by TS-24. Furthermore, TS-24 demonstrated the additional effect of inhibiting cell migration. Our study suggests that employing CTSS inhibitors for the functional restoration of BRCA1 to enhance RT-induced apoptosis may provide a novel therapeutic opportunity for TNBC patients harboring wild-type BRCA1.

Exploring Piperine: Unleashing the multifaceted potential of a phytochemical in cancer therapy.

Radiotherapy is a cornerstone in the treatment of solid tumors, with extensive Phase III trials confirming its effectiveness. As advancements in treatment technologies and our understanding of tumor resistance mechanisms continue, the role of radiation oncology is set to become even more pivotal. Addressing the global challenge of lethal cancers demands innovative strategies, particularly in minimizing the side effects associated with traditional chemotherapy and ionizing radiation (IR). Recently, there has been growing interest in natural compounds for radioprotection, aiming to prevent tumor development and metastasis. Piperine, a compound found in black and long pepper, has emerged as a promising chemopreventive agent that works effectively without harming normal cells. Mechanistically, piperine modulates key signaling pathways, inhibits cancer cell migration and invasion, and enhances sensitivity to IR. Combining piperine with radiotherapy offers a compelling approach, boosting treatment efficacy while protecting healthy tissues from radiation damage. Piperine's versatile role goes beyond radiosensitization to include radioprotection by inhibiting NF-κB activation, reducing autophagy, and promoting apoptosis in cancer cells. This dual action makes it a promising candidate for personalized cancer care. As research advances, the therapeutic potential of piperine may drive new frontiers in cancer treatment strategies.

Assembling Au8 clusters on surfaces of bifunctional nanoimmunomodulators for synergistically enhanced low dose radiotherapy of metastatic tumor.

BACKGROUND: Radiotherapy is one of the mainstays of cancer therapy and has been used for treating 65-75% of patients with solid tumors. However, radiotherapy of tumors has two limitations: high-dose X-rays damage adjacent normal tissue and tumor metastases cannot be prevented. RESULTS: Therefore, to overcome the two limitations of radiotherapy, a multifunctional core-shell R837/BMS@Au8 nanoparticles as a novel radiosensitizer were fabricated by assembling Au8NCs on the surface of a bifunctional nanoimmunomodulator R837/BMS nanocore using nanoprecipitation followed by electrostatic assembly. Formed R837/BMS@Au8 NP composed of R837, BMS-1, and Au8 clusters. Au8NC can enhance X-ray absorption at the tumor site to reduce X-ray dose and releases a large number of tumor-associated antigens under X-ray irradiation. With the help of immune adjuvant R837, dendritic cells can effectively process and present tumor-associated antigens to activate effector T cells, meanwhile, a small-molecule PD-L1 inhibitor BMS-1 can block PD-1/PD-L1 pathway to reactivate cytotoxic T lymphocyte, resulting in a strong systemic antitumor immune response that is beneficial for limiting tumor metastasis. According to in vivo and in vitro experiments, radioimmunotherapy based on R837/BMS@Au8 nanoparticles can increase calreticulin expression on of cancer cells, reactive oxygen species generation, and DNA breakage and decrease colony formation. The results revealed that distant tumors were 78.2% inhibited depending on radioimmunotherapy of primary tumors. Therefore, the use of a novel radiosensitizer R837/BMS@Au8 NPs realizes low-dose radiotherapy combined with immunotherapy against advanced cancer. CONCLUSION: In conclusion, the multifunctional core-shell R837/BMS@Au8 nanoparticles as a novel radiosensitizer effectively limiting tumor metastasis and decrease X-ray dose to 1 Gy, providing an efective strategy for the construction of nanosystems with radiosensitizing function.

Novel Amidine Derivative K1586 Sensitizes Colorectal Cancer Cells to Ionizing Radiation by Inducing Chk1 Instability.

Checkpoint kinase 1 (Chk1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair, and DNA replication. Small-molecule Chk1 inhibitors sensitize cancer cells to genotoxic agents and have shown preclinical activity as single agents in cancers characterized by high levels of replication stress. However, the underlying genetic determinants of Chk1-inhibitor sensitivity remain unclear. Although treatment options for advanced colorectal cancer are limited, radiotherapy is effective. Here, we report that exposure to a novel amidine derivative, K1586, leads to an initial reduction in the proliferative potential of colorectal cancer cells. Cell cycle analysis revealed that the length of the G2/M phase increased with K1586 exposure as a result of Chk1 instability. Exposure to K1586 enhanced the degradation of Chk1 in a time- and dose-dependent manner, increasing replication stress and sensitizing colorectal cancer cells to radiation. Taken together, the results suggest that a novel amidine derivative may have potential as a radiotherapy-sensitization agent that targets Chk1.

Application of High-Z Nanoparticles to Enhance Current Radiotherapy Treatment.

Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques, the dose escalation required to enhance tumor control is limited due to the inevitable toxicity to the surrounding healthy tissue. Therefore, the local enhancement of dosing in tumor sites can provide the necessary means to improve the treatment modality. In recent years, the emergence of nanotechnology has facilitated a unique opportunity to increase the efficacy of radiotherapy treatment. The application of high-atomic-number (Z) nanoparticles (NPs) can augment the effects of radiotherapy by increasing the sensitivity of cells to radiation. High-Z NPs can inherently act as radiosensitizers as well as serve as targeted delivery vehicles for radiosensitizing agents. In this work, the therapeutic benefits of high-Z NPs as radiosensitizers, such as their tumor-targeting capabilities and their mechanisms of sensitization, are discussed. Preclinical data supporting their application in radiotherapy treatment as well as the status of their clinical translation will be presented.

Combination therapy with hydrogen peroxide and irradiation promotes an abscopal effect in mouse models.

Hydrogen peroxide (H2 O2 ) induces oxidative stress and cytotoxicity, and can be used for treating cancers in combination with radiotherapy. A product comprising H2 O2 and sodium hyaluronate has been developed as a radiosensitizer. However, the effects of H2 O2 on antitumor immunity remain unclear. To investigate the effects of H2 O2 , especially the abscopal effect when combined with radiotherapy (RT), we implanted murine tumor cells simultaneously in two locations in mouse models: the hind limb and back. H2 O2 mixed with sodium hyaluronate was injected intratumorally, followed by irradiation only at the hind limb lesion. No treatment was administered to the back lesion. The H2 O2 /RT combination significantly reduced tumor growth at the noninjected/nonirradiated site in the back lesion, whereas H2 O2 or RT individually did not reduce tumor growth. Flow cytometric analyses of the tumor-draining lymph nodes in the injected/irradiated areas showed that the number of dendritic cells increased significantly with maturation in the H2 O2 /RT combination group. In addition, analyses of tumor-infiltrating lymphocytes showed that the number of CD8+ (cluster of differentiation 8) T cells and the frequency of IFN-γ+ (interferon gamma) CD8+ T cells were higher in the noninjected/nonirradiated tumors in the H2 O2 /RT group compared to those in the other groups. PD-1 (programmed death receptor 1) blockade further increased the antitumor effect against noninjected/nonirradiated tumors in the H2 O2 /RT group. Intratumoral injection of H2 O2 combined with RT therefore induces an abscopal effect by activating antitumor immunity, which can be further enhanced by PD-1 blockade. These findings promote the development of H2 O2 /RT therapy combined with cancer immunotherapies, even for advanced cancers.

Prognostic biomarkers for the response to the radiosensitizer nimorazole combined with RCTx: a pre-clinical trial in HNSCC xenografts.

BACKGROUND: Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined with radiotherapy (RT) enabled to improve loco-regional control (LRC) in some patients with hypoxic tumors but it is unknown whether this holds also for radiochemotherapy (RCTx). Here, we investigated the impact of nimorazole combined with RCTx in HNSCC xenografts and explored molecular biomarkers for its targeted use. METHODS: Irradiations were performed with 30 fractions in 6 weeks combined with weekly cisplatin. Nimorazole was applied before each fraction, beginning with the first or after ten fractions. Effect of RCTx with or without addition of nimorazole was quantified as permanent local control after irradiation. For histological evaluation and targeted gene expression analysis, tumors were excised untreated or after ten fractions. Using quantitative image analysis, micromilieu parameters were determined. RESULTS: Nimorazole combined with RCTx significantly improved permanent local control in two tumor models, and showed a potential improvement in two additional models. In these four models, pimonidazole hypoxic volume (pHV) was significantly reduced after ten fractions of RCTx alone. Our results suggest that nimorazole combined with RCTx might improve TCR compared to RCTx alone if hypoxia is decreased during the course of RCTx but further experiments are warranted to verify this association. Differential gene expression analysis revealed 12 genes as potential for RCTx response. When evaluated in patients with HNSCC who were treated with primary RCTx, these genes were predictive for LRC. CONCLUSIONS: Nimorazole combined with RCTx improved local tumor control in some but not in all HNSCC xenografts. We identified prognostic biomarkers with the potential for translation to patients with HNSCC.

Multifunctional Dendritic Au@SPP@DOX Nanoparticles Integrating Chemotherapy and Low-Dose Radiotherapy for Enhanced Anticancer Activity.

Combined chemoradiotherapy can improve antitumor efficiency and reduce the side effects of monotherapy. In this study, we aimed to construct dendritic peptide-based multifunctional nanoparticles (Au@SPP@DOX) for a prolonged circulation time, enhanced cellular uptake, and targeted cancer therapy. Amphiphilic micelle PEG-polylysine-SA (SPP) is composed of polylysine combined with hydrophilic poly(ethylene glycol) (PEG) and hydrophobic stearic acid (SA). Doxorubicin (DOX) is loaded via the hydrophilic-hydrophobic interaction of SPP, and gold nanoparticles (AuNPs) are loaded via the electrostatic interaction with SPP. Au@SPP@DOX showed good biocompatibility and could be successfully accumulated at tumor sites through the enhanced permeability and retention (EPR) effect. Then, lysosomes could be ruptured due to the proton sponge effect. DOX became protonated in response to tumor extracellular acidity and was then released from SPP. Under the action of low-dose radiation, Au@SPP@DOX could promote the production of reactive oxygen species (ROS), increase mitochondrial dysfunction, block cell division, and ultimately promote tumor cell apoptosis to achieve a better antitumor effect. This study highlighted the benefit of chemoradiotherapy and suggested that Au@SPP@DOX might serve as a high-efficiency codelivery system for cancer combination therapy in the future.

7-Geranyloxcycoumarin enhances radio sensitivity in human prostate cancer cells.

BACKGROUND: Prostate cancer is the second most prevalent and the fifth deadliest cancer among men worldwide. To improve radiotherapy outcome, we investigated the effects of 7-geranyloxycoumarin, also known as auraptene (AUR), on radiation response of prostate cancer cells. METHODS AND RESULTS: PC3 cells were pretreated with 20 and 40 µM AUR for 24, 48 and 72 h, followed by X-ray exposure (2, 4 and 6 Gy). After 72 h recovery, cell viability was determined by alamar Blue assay. Flow cytometric analysis was performed to assess apoptosis induction, clonogenic assay was carried out to investigate clonogenic survival, and the expression of P53, BAX, BCL2, CCND1 and GATA6 was analyzed by quantitative polymerase chain reaction (qPCR). Cell viability assay indicated that toxic effects of radiation was enhanced by AUR, which was also confirmed by increased numbers of apoptotic cells and reduced amount of survival fraction. The qPCR results demonstrated significant induction of P53 and BAX, while the expression of BCL2, GATA6, and CCND1 was significantly downregulated. CONCLUSION: The findings of the present study indicated, for the first time, that AUR improved radio sensitivity in prostate cancer cells, and thus, has the potential to be used in future clinical trials.

Alleviating the hypoxic tumor microenvironment with MnO2-coated CeO2 nanoplatform for magnetic resonance imaging guided radiotherapy.

BACKGROUND: Radiotherapy is a commonly used tool in clinical practice to treat solid tumors. However, due to the unique microenvironment inside the tumor, such as high levels of GSH, overexpressed H2O2 and hypoxia, these factors can seriously affect the effectiveness of radiotherapy. RESULTS: Therefore, to further improve the efficiency of radiotherapy, a core-shell nanocomposite CeO2-MnO2 is designed as a novel radiosensitizer that can modulate the tumor microenvironment (TME) and thus improve the efficacy of radiation therapy. CeO2-MnO2 can act as a radiosensitizer to enhance X-ray absorption at the tumor site while triggering the response behavior associated with the tumor microenvironment. According to in vivo and in vitro experiments, the nanoparticles aggravate the killing effect on tumor cells by generating large amounts of ROS and disrupting the redox balance. In this process, the outer layer of MnO2 reacts with GSH and H2O2 in the tumor microenvironment to generate ROS and release oxygen, thus alleviating the hypoxic condition in the tumor area. Meanwhile, the manganese ions produced by degradation can enhance T1-weighted magnetic resonance imaging (MRI). In addition, CeO2-MnO2, due to its high atomic number oxide CeO2, releases a large number of electrons under the effect of radiotherapy, which further reacts with intracellular molecules to produce reactive oxygen species and enhances the killing effect on tumor cells, thus having the effect of radiotherapy sensitization. In conclusion, the nanomaterial CeO2-MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystem with radiosensitizing function. CONCLUSION: In conclusion, the nanomaterial CeO2-MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystems with radiosensitizing function.

Targeting TGF beta receptor 1 in head and neck squamous cell carcinoma.

OBJECTIVES: The transforming growth factor-Beta (TGF-ß) pathway may be involved in the radioresistance of head and neck squamous cell carcinoma (HNSCC). This study analyzed TGF-ß receptor 1 (TGFBR1) expression in HNSCC patients and evaluated the antineoplastic and radiosensitizing effects of vactosertib, a novel TGFBR1 inhibitor, in vitro. MATERIALS AND METHODS: TGFBR1 expression was examined in HNSCC patients at the mRNA level in silico and the protein level by immunohistochemistry, including surgical specimens of primary tumors, matched lymph node metastasis, and recurrent disease. Furthermore, a novel small molecule TGFBR1 inhibitor was evaluated in HNSCC cell lines. Finally, an indirect coculture model using patient-derived cancer-associated fibroblasts was applied to mimic the tumor microenvironment. RESULTS: Patients with high TGFBR1 mRNA levels showed significantly worse overall survival in silico (OS, p = 0.024). At the protein level, an association between TGFBR1+ tumor and OS was observed for the subgroup with TGFBR1-stroma (p = 0.001). Those results prevailed in multivariable analysis. Inhibition of TGFBR1 showed antineoplastic effects in vitro. In combination with radiation, vactosertib showed synergistic effects. CONCLUSION: Our results indicate a high risk of death in tumorTGFBR1+ |stromaTGFBR1- expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib.

Radiosensitizing Effects of Irinotecan versus Oxaliplatin Alone and in Combination with 5-Fluorouracil on Human Colorectal Cancer Cells.

To date, oxaliplatin and irinotecan are used in combination with 5-flourouracil (5-FU) for metastatic colorectal cancer. In this study it was tested whether oxaliplatin and irinotecan and their combinations with 5-FU have an enhanced effect when treated simultaneously with ionizing radiation. In addition, it should be compared whether one combination therapy is more effective than the other. Colorectal cancer cells (HT-29) were treated with irinotecan or oxaliplatin, both alone and in combination with 5-FU, and subsequently irradiated. The cell growth, metabolic activity and proliferation of cells were investigated, and the clonogenic survival was determined. Furthermore, the assessment of radiation-induced DNA damage and the influence of the drugs and their combinations on DNA damage repair was investigated. Treatment with irinotecan or oxaliplatin in combination with 5-FU inhibited proliferation and metabolic activity as well as clonogenic survival and the DNA damage repair capacity of the tumor cells. The comparison of oxaliplatin and irinotecan with simultaneous irradiation showed the same effect of both drugs. When oxaliplatin or irinotecan was combined with 5-FU, tumor cell survival was significantly lower than with monotherapy; however, there was no superiority of either combination regimen. Our results have shown that the combination of 5-FU and irinotecan is as effective as the combination of 5-FU with oxaliplatin. Therefore, our data support the use of FOLFIRI as a radiosensitizer.

A Cell-Penetrating Peptide Modified Cu2-xSe/Au Nanohybrid with Enhanced Efficacy for Combined Radio-Photothermal Therapy.

Radiotherapy (RT) is one of the main clinical therapeutic strategies against cancer. Currently, multiple radiosensitizers aimed at enhancing X-ray absorption in cancer tissues have been developed, while limitations still exist for their further applications, such as poor cellular uptake, hypoxia-induced radioresistance, and unavoidable damage to adjacent normal body tissues. In order to address these problems, a cell-penetrating TAT peptide (YGRKKRRQRRRC)-modified nanohybrid was constructed by doping high-Z element Au in hollow semiconductor Cu2-xSe nanoparticles for combined RT and photothermal therapy (PTT) against breast cancer. The obtained Cu2-xSe nanoparticles possessed excellent radiosensitizing properties based on their particular band structures, and high photothermal conversion efficiency beneficial for tumor ablation and promoting RT efficacy. Further doping high-Z element Au deposited more high-energy radiation for better radiosensitizing performance. Conjugation of TAT peptides outside the constructed Cu2-xSe/Au nanoparticles facilitated their cellular uptake, thus reducing overdosage-induced side effects. This prepared multifunctional nanohybrid showed powerful suppression effects towards breast cancer, both in vitro and in vivo via integrating enhanced cell penetration and uptake, and combined RT/PTT strategies.

Dose-enhancement of MCF 7 cell line radiotherapy using silica-iron oxide nanocomposite.

Cancer radiotherapy is one of the most effective regimens of cancer treatments, but cancer cell radioresistance remains a concern. Radiosensitizers can selectively improve the efficacy of radiotherapy and reduce inherent damage. The purpose of this work is to evaluate the effect of silica-coated iron oxide magnetic nanoparticles (SIONPs) as a radiosensitizer and compare their therapeutic effect with that of Iron oxide magnetic nanoparticles (IONPs). IONPs and SIONPs were characterized using several physical techniques such as a transmission electron microscope (TEM) and Vibrating sample magnetometer (VSM). MTT and DNA double-strand breaks (Comet) assays have been used to detect the cytotoxicity, cell viability, and DNA damage of MCF-7 cells, which were treated with different concentrations of prepared nanoparticles and exposed to an X-ray beam. In this study, an efficient radiosensitizer, SIONPs, was successfully prepared and characterized. With 0.5 Gy dose, dose enhancement factor (DEF) values of cells treated with 5 and 10 µg/ml of IONPs were 1 and 1.09, respectively, while those treated with SIONPs at these concentrations had DEF of 1.21 and 1.32, respectively. Results demonstrated that SIONPs provide a potential for improving the radiosensitivity of breast cancer.

The use of radiosensitizing agents in the therapy of glioblastoma multiforme-a comprehensive review.

BACKGROUND: Glioblastoma is the most common malignant brain tumor in human adults. Despite several improvements in resective as well as adjuvant therapy over the last decades, its overall prognosis remains poor. As a means of improving patient outcome, the possibility of enhancing radiation response by using radiosensitizing agents has been tested in an array of studies. METHODS: A comprehensive review of clinical trials involving radiation therapy in combination with radiosensitizing agents on patients diagnosed with glioblastoma was performed in the National Center for Biotechnology Information's PubMed database. RESULTS: A total of 96 papers addressing this matter were published between 1976 and 2021, of which 63 matched the subject of this paper. All papers were reviewed, and their findings discussed in the context of their underlining mechanisms of radiosensitization. CONCLUSION: In the history of glioblastoma treatment, several approaches of optimizing radiation-effectiveness using radiosensitizers have been made. Even though several different strategies and agents have been explored, clear evidence of improved patient outcome is still missing. Tissue-selectiveness and penetration of the blood-brain barrier seem to be major roadblocks; nevertheless, modern strategies try to circumvent these obstacles, using novel sensitizers based on preclinical data or alternative ways of delivery.

Exposure-response modeling improves selection of radiation and radiosensitizer combinations.

A central question in drug discovery is how to select drug candidates from a large number of available compounds. This analysis presents a model-based approach for comparing and ranking combinations of radiation and radiosensitizers. The approach is quantitative and based on the previously-derived Tumor Static Exposure (TSE) concept. Combinations of radiation and radiosensitizers are evaluated based on their ability to induce tumor regression relative to toxicity and other potential costs. The approach is presented in the form of a case study where the objective is to find the most promising candidate out of three radiosensitizing agents. Data from a xenograft study is described using a nonlinear mixed-effects modeling approach and a previously-published tumor model for radiation and radiosensitizing agents. First, the most promising candidate is chosen under the assumption that all compounds are equally toxic. The impact of toxicity in compound selection is then illustrated by assuming that one compound is more toxic than the others, leading to a different choice of candidate.

Development of tumor-specific liposomes containing quantum dots-photosensitizer conjugate used for radiotherapy.

This study aims to develop a multifunctional liposomal radiosensitizer to destroy more tumor cells by using lower radiation doses compared to clinically used 6 MV X-ray doses. To achieve this aim, first Chlorine-e6 (Ce6) was covalently bound to functional groups of outer surfaces of quantum dots (QDs) through EDC/NHS reactions. Then, QDs-Ce6 conjugate loaded, nanosized, PEG-coated, and tumor-specific folic acid-modified immunoliposome dispersions were prepared by film method. Enhanced anti-proliferation activity of free and liposomal conjugate against 4T1 (murine breast cancer) cell lines was investigated at different X-ray doses (5, 10, 15, and 20 Gy). As a result, the best radiosensitizer effect was observed at a 5 Gy X-ray dose and it was found that following the X-ray irradiation, immunoliposome dispersions containing QDs-Ce6 conjugate killed 26.8 ± 1.7% more cancer cells than radiation alone.

Dose Rate Effects on the Selective Radiosensitization of Prostate Cells by GRPR-Targeted Gold Nanoparticles.

For a while, gold nanoparticles (AuNPs) have been recognized as potential radiosensitizers in cancer radiation therapy, mainly due to their physical properties, making them appealing for medical applications. Nevertheless, the performance of AuNPs as radiosensitizers still raises important questions that need further investigation. Searching for selective prostate (PCa) radiosensitizing agents, we studied the radiosensitization capability of the target-specific AuNP-BBN in cancer versus non-cancerous prostate cells, including the evaluation of dose rate effects in comparison with non-targeted counterparts (AuNP-TDOTA). PCa cells were found to exhibit increased AuNP uptake when compared to non-tumoral ones, leading to a significant loss of cellular proliferation ability and complex DNA damage, evidenced by the occurrence of multiple micronucleus per binucleated cell, in the case of PC3 cells irradiated with 2 Gy of γ-rays, after incubation with AuNP-BBN. Remarkably, the treatment of the PC3 cells with AuNP-BBN led to a much stronger influence of the dose rate on the cellular survival upon γ-photon irradiation, as well as on their genomic instability. Overall, AuNP-BBN emerged in this study as a very promising nanotool for the efficient and selective radiosensitization of human prostate cancer PC3 cells, therefore deserving further preclinical evaluation in adequate animal models for prostate cancer radiotherapy.

Influence of Hypoxia on Radiosensitization of Cancer Cells by 5-Bromo-2'-deoxyuridine.

Radiotherapy is a crucial cancer treatment, but its outcome is still far from satisfactory. One of the reasons that cancer cells show resistance to ionizing radiation is hypoxia, defined as a low level of oxygenation, which is typical for solid tumors. In the hypoxic environment, cancer cells are 2-3 times more resistant to ionizing radiation than normoxic cells. To overcome this important impediment, radiosensitizers should be introduced to cancer therapy. When modified with an electrophilic substituent, nucleosides may undergo efficient dissociative electron attachment (DEA) that leaves behind nucleoside radicals, which, in secondary reactions, are able to induce DNA damage, leading to cancer cell death. We report the radiosensitizing effect of one of the best-known DEA-type radiosensitizers-5-bromo-2'-deoxyuridine (BrdU)-on breast (MCF-7) and prostate (PC3) cancer cells under both normoxia and hypoxia. MCF-7 and PC3 cells were treated with BrdU to investigate the effect of hypoxia on cell proliferation, incorporation into DNA and radiosensitivity. While the oxygen concentration did not significantly affect the efficiency of BrdU incorporation into DNA or the proliferation of tumor cells, the radiosensitizing effect of BrdU on hypoxic cells was more evident than on normoxic cells. Further mechanistic studies performed with the use of flow cytometry showed that under hypoxia, BrdU increased the level of histone H2A.X phosphorylation after X-ray exposure to a greater extent than under normal oxygenation conditions. These results confirm that the formation of double-strand breaks in hypoxic BrdU-treated cancer cells is more efficient. In addition, by performing stationary radiolysis of BrdU solution in the presence of an ●OH radical scavenger, we compared the degree of its electron-induced degradation under aerobic and anaerobic conditions. It was determined that radiodegradation under anaerobic conditions was almost twice as high as that under aerobic conditions.

Natural Radiosensitizers in Radiotherapy: Cancer Treatment by Combining Ionizing Radiation with Resveratrol.

Conventional cancer treatment is mainly based on the surgical removal of the tumor followed by radiotherapy and/or chemotherapy. When surgical removal is not possible, radiotherapy and, less often, chemotherapy is the only way to treat patients. However, despite significant progress in understanding the molecular mechanisms of carcinogenesis and developments in modern radiotherapy techniques, radiotherapy (alone or in combination) does not always guarantee treatment success. One of the main causes is the radioresistance of cancer cells. Increasing the radiosensitivity of cancer cells improves the processes leading to their elimination during radiotherapy and prolonging the survival of cancer patients. In order to enhance the effect of radiotherapy in the treatment of radioresistant neoplasms, radiosensitizers are used. In clinical practice, synthetic radiosensitizers are commonly applied, but scientists have recently focused on using natural products (phytocompounds) as adjuvants in radiotherapy. In this review article, we only discuss naturally occurring radiosensitizers currently in clinical trials (paclitaxel, curcumin, genistein, and papaverine) and those whose radiation sensitizing effects, such as resveratrol, have been repeatedly confirmed by many independent studies.