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Radiation therapy (RT) is frequently used to locally treat tumors. One of the major issues in RT is normal tissue toxicity; thus, it is necessary to limit dose escalation for enhanced local control in patients that have locally advanced tumors. Integrating radiosensitizing agents such as gold nanoparticles (GNPs) into RT has been shown to greatly increase the cure rate of solid tumors. The objective of this study was to explore the repurposing of an antimalarial drug, pyronaridine (PYD), as a DNA repair inhibitor to further enhance RT/GNP-induced DNA damage in cancerous cell lines. We were able to achieve inhibitory effects of DNA repair due to PYD at 500 nM concentration. Our results show a significant enhancement in DNA double-strand breaks of 42% in HeLa cells treated with PYD/GNP/RT in comparison to GNP/RT alone when irradiated with a dose of 2 Gy. Furthermore, there was a significant reduction in cellular proliferation for both HeLa and HCT-116 irradiated cells with the combined treatment of PYD/GNP/RT. Therefore, the emergence of promising novel concepts introduced in this study could lay the foundation for the transition of this treatment modality into clinical environments. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiation-based anticancer therapies are often ineffective as cancer cells may acquire radioresistance. Moreover, such therapies can cause unwanted side effects, affecting normal tissues. This problem may be remedied by the use of nanometric radiosensitizers. These compounds in non-toxic concentrations improve the effectiveness of therapy while reducing the total dose of radiation used. In this work, we checked the radiosensitizing properties of bimetallic palladium-platinum nanoparticles with different nanostructures: nano-alloy and core-shell. It has been found that nano-alloy structures are more promising radiosensitizers in vitro, and their effect is more satisfactory when using X-rays than high-energy protons. Thus, by appropriately designing the microstructure of nanomaterials, it is possible to modulate their radiosensitizing potential and enhance the therapy′s effectiveness. Nano-sized radiosensitizers can be used to increase the effectiveness of radiation-based anticancer therapies. In this study, bimetallic, ~30 nm palladium-platinum nanoparticles (PdPt NPs) with different nanostructures (random nano-alloy NPs and ordered core-shell NPs) were prepared. Scanning transmission electron microscopy (STEM), selected area electron diffraction (SAED), energy-dispersive X-ray spectroscopy (EDS), zeta potential measurements, and nanoparticle tracking analysis (NTA) were used to provide the physicochemical characteristics of PdPt NPs. Then, PdPt NPs were added to the cultures of colon cancer cells and normal colon epithelium cells in individually established non-toxic concentrations and irradiated with the non-harmful dose of X-rays/protons. Cell viability before and after PdPt NPs-(non) assisted X-ray/proton irradiation was evaluated by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Flow cytometry was used to assess cell apoptosis. The results showed that PdPt NPs significantly enhanced the effect of irradiation on cancer cells. It was noticed that nano-alloy PdPt NPs possess better radiosensitizing properties compared to PtPd core-shell NPs, and the combined effect against cancer cells was c.a. 10% stronger for X-ray than for proton irradiation. Thus, the radio-enhancing features of differently structured PdPt NPs indicate their potential application for the improvement of the effectiveness of radiation-based anticancer therapies. [ABSTRACT FROM AUTHOR]

Friction coefficient behaviour of electron beam cured vinylidene fluoride-hexafluoropropylene copolymer fluorocarbon rubber (FKM) with 30% loading of polytetrafluoroethylene micro-powder (PTFEMP) irradiated at 250 kGy dose were studied by using a pin-on-disk tribometer for a total testing distance of 360 m in dry conditions at a sliding speed and applied normal load (F N) of 0.05 m/s and 1 N respectively. The same tests were done on the 70/30 blend added with radiation sensitizers n,n-1,3 phenylene bismaleimide (HVA2), trimethylol propane triacrylate (TMPTA) and tripropylene glycol diacrylate (TPGDA). The average friction coefficient (μ) value of all the composites with sensitizer decreased with the TMPTA system recording the lowest μ value which reduced by almost half compared to the pure composite due to better crosslinking density of the vulcanizate. Analysis of the friction coefficient curve behaviour showed an initial low value but displaying an increasing trend versus distance in the TMPTA and TPGDA composites while HVA2 composite recorded an initial high value but showed a reducing trend versus distance. HVA2 composite also recorded the best tensile strength results due to its influence in promoting better synergistic effect and miscibility of PTFEMP filler in FKM matrix. • Radiation sensitizer promotes crosslinking in electron beam cured FKM-PTFE composite. • Friction coefficient of irradiated FKM-PTFE composite reduced with the use radiation sensitizer. • Thermal stability of irradiated FKM-PTFE composite improved with the use of radiation sensitizer. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) eliminates tumor cells by high doses of radiation causing DNA damage. However, some tumor cells are reported with radiation resistance that can compromise the efficacy of RT. Cyclin Dependent Kinase Inhibitor 1A (CDKN1A or p21) is a gene associated with the regulation of cell cycle, including DNA damage repair mechanism. The resistance can be a result brought by the suppression of CDKN1A expression. Preliminarily, a stress-responsive protein, Musashi-1, was found to inhibit CDKN1A through direct 3'UTR binding. Therefore, this study aims to develop a radiosensitizer screening platform utilizing the Musashi-1-CDKN1A regulatory circuit to speed up the discovery of novel anti-cancer therapy. Glioblastoma (GBM) cells with wild-type and loss-of-phosphorylation Musashi-1 were established by lentiviral infection. The radiosensitivity was assessed by clonogenic assays. Comet Assay was performed to quantitatively compare DNA damage levels. Western blots were used for the assessment of protein levels in different conditions. A renilla luciferase-based CDKN1A 3'UTR reporter system was obtained from Dr. Gorospe and was subjected to molecular cloning to magnify the bioluminescent signal. Musashi-1 is proved to be oncogenic in clonogenic assays and the subsequent radiation resistance. However, most oncogenic behaviors were eliminated when the phosphorylation site is mutant. The protein level of CDKN1A was enhanced with Musashi-1 loss-of-phosphorylation. However, mRNA and Musashi-1-bound RNA remain unchanged, suggesting a translational regulation may occur. The tail moment in the comet assay suggested the enhancement of radiosensitivity when Musashi-1 phosphorylation is deprived. Our study indicated that the phosphorylation of Musashi-1 can be a therapeutic target due to its ability to hinder the DNA repair mechanisms of GBM cells. To further exploit this mechanism, a luciferase reporter system can be established to screen for potential radiosensitizers, such as kinase inhibitors that can prevent the phosphorylation of Musashi-1 to increase the efficacy of RT treatment. [ABSTRACT FROM AUTHOR]

• Increased APE1 redox activity and ATM activation exist in OS after IR. • Dual inhibition of APE1 redox activity and ATM activation sensitizes OS to IR. • Dual inhibition of APE1 redox activity and ATM activation induces ferroptosis via p53. The resistance of osteosarcoma (OS) to ionizing radiation (IR) is an obstacle for effective patient treatment. Apurinic/apyrimidinic endonuclease-reduction/oxidation factor 1 (APE1/Ref-1) is a multifunctional protein with DNA repair and reduction/oxidation (redox) activities. We previously revealed the role of APE1 in OS radioresistance; however, whether the redox activity of APE1 is involved in OS radioresistance is unclear. APE1 regulates the activation of ataxia-telangiectasia mutated (ATM), an initiator of DNA damage response that mediates radioresistance in other cancers. The role of APE1 redox activity and ATM activation in OS radioresistance is unknown. Our study revealed that IR increased APE1 expression and ATM activation in OS cells, and APE1 directly regulated ATM activation by its redox activity. The combined use of an APE1 redox inhibitor and ATM inhibitor effectively sensitized OS cells to IR in vitro and in vivo. Mechanistically, the increased radiosensitization of OS cells by the combined use of the two inhibitors was mediated by increased ferroptosis. Co-treatment with the two inhibitors significantly decreased expression of the common targeted transcription factor P53 compared with single inhibitor treatment. Collectively, APE1 redox activity, ATM activation and their crosstalk play important roles in the resistance of OS to irradiation. Synergetic inhibition of APE1 redox activity and ATM activation sensitized OS cells to IR by inducing ferroptosis, which provides a promising strategy for OS radiotherapy. [ABSTRACT FROM AUTHOR]

A method of straightforward construction and analysis of the cascade decay trees is applied to study the cascade energy reemission by silver atoms upon photoionization in the incident photon energy range of 0.01–100 keV. Cascade electrons and photons emitted during the cascade relaxation of an inner-shell vacancy carry away a significant part of the energy initially acquired by the silver atom in a photoionization act. The energies redistributed through following channels were calculated as functions of incident photon energy: energy absorbed by the silver atom itself (a), and energies carried away by the cascade electrons (b) and photons (c). Channel (a) is dominant only at small incident photon energies up to the M 5 ionization threshold. Channel (b) dominates between M and K thresholds making 57–85 % of the acquired energy. Above the K threshold, the weight of channel (b) is still significant, 24 %, however, dominant is channel (c). • Cascade energy reemission by silver atoms upon photoionization are simulated. • Most of the absorbed photon energy is re-emitted with cascade electrons and photons. • Application of Ag-based radiosensitizers in photon beam radiotherapy is discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] • MRgFUS-MB upregulates apoptotic pathways and enhances radiation-induced cell death. • Phase 1 clinical trial: enrolled 12 stage HN cancer patients undergoing radiotherapy. • Patients underwent 2–3 MRgFUS-MB treatments during their radiotherapy regimen. • Safety: no systemic toxicity or MRgFUS-MB-related adverse events occurred. • Tumour response: 87.5 % partial or complete responses at 3 months. Preclinical research demonstrated that the exposure of microbubbles (intravascular gas microspheres) to focussed ultrasound within the targeted tumour upregulates pro-apoptotic pathways and enhances radiation-induced tumour cell death. This study aimed to assess the safety and efficacy of magnetic resonance (MR)-guided focussed ultrasound-stimulated microbubbles (MRgFUS-MB) for head and neck cancers (HN). This prospective phase 1 clinical trial included patients with newly diagnosed or recurrent HN cancer (except nasopharynx malignancies) for whom locoregional radiotherapy with radical- or palliative-intent as deemed appropriate. Patients with contraindications for microbubble administration or contrast-enhanced MR were excluded. MR-coupled focussed ultrasound sonicated intravenously administered microbubbles within the MR-guided target volume. Patients receiving 5–10 and 33–35 radiation fractions were planned for 2 and 3 MRgFUS-MB treatments, respectively. Primary endpoint was toxicity per CTCAEv5.0. Secondary endpoint was tumour response at 3 months per RECIST 1.1 criteria. Twelve patients were enrolled between Jun/2020 and Nov/2023, but 1 withdrew consent. Eleven patients were included in safety analysis. Median follow-up was 7 months (range, 0.3–38). Most patients had oropharyngeal cancer (55 %) and received 20–30 Gy/5–10 fractions (63 %). No systemic toxicity or MRgFUS-MB-related adverse events occurred. The most severe acute adverse events were radiation-related grade 3 toxicities in 6 patients (55 %; dermatitis in 3, mucositis in 1, dysphagia in 6). No radiation necrosis or grade 4/5 toxicities were reported. 8 patients were included in the 3-month tumour response assessment: 4 had partial response (50 %), 3 had complete response (37.5 %), and 1 had progressive disease (12.5 %). MRgFUS-MB treatment was safe and associated with high rates of tumour response at 3 months. [ABSTRACT FROM AUTHOR]

Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFκB/FOXM1 protected from CUDC-907-induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFκB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG.Significance: These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. Cancer Res; 78(14); 4007-21. ©2018 AACR.

5-trifluoromethanesulfonyl-uracil (OTfU), a recently proposed radiosensitizer, is decomposed in the gas-phase by attachment of low-energy electrons. OTfU is a derivative of uracil with a triflate (OTf) group at the C5-position, which substantially increases its ability to undergo effective electron-induced dissociation. We report a rich assortment of fragments formed upon dissociative electron attachment (DEA), mostly by simple bond cleavages (e.g., dehydrogenation or formation of OTf−). The most favorable DEA channel corresponds to the formation of the triflate anion alongside with the reactive uracil-5-yl radical through the cleavage of the O–C5 bond, particularly at about 0 eV. Unlike for halouracils, the parent anion was not detected in our experiments. The experimental findings are accounted by a comprehensive theoretical study carried out at the M06-2X/aug-cc-pVTZ level. The latter comprises the thermodynamic thresholds for the formation of the observed anions calculated under the experimental conditions (383.15 K and 3 × 10−11 atm). The energy-resolved ion yield of the dehydrogenated parent anion, (OTfU–H)−, is discussed in terms of vibrational Feshbach resonances arising from the coupling between the dipole bound state and vibrational levels of the transient negative ion. We also report the mass spectrum of the cations obtained through ionization of OTfU by electrons with a kinetic energy of 70 eV. The current study endorses OTfU as a potential radiosensitizer agent with possible applications in radio-chemotherapy. [ABSTRACT FROM AUTHOR]

Due to its non-invasive and highly effective characteristics, radiotherapy has attracted significant interest in cancer treatment. However, radioresistance of solid tumors caused by a unique tumor microenvironment diminishes the therapeutic effect of cancer radiotherapy. To address this issue, we developed a nanoplatform for tumor-specific targeting to improve radiotherapy. Specifically, hollow CuS nanoparticles were decorated with the platelet cell membrane (PC), endowing this nanoplatform with the therapeutic property of navigating to the tumor region for glutathione (GSH)-depletion photothermal therapy. It was discovered that mild photothermal therapy mediated by PC ameliorated hypoxia in the tumor microenvironment. Meanwhile, GSH, which contributes to repairing radiotherapy-induced DNA double-strand breaks, was depleted by PC in an acidic microenvironment. Therefore, radioresistance could be diminished while cancer cell self-repair was prevented. At therapeutic doses, PC nanoparticles have negligible toxic effects on normal tissues. PC demonstrates promise for both in vivo and in vitro radiosensitization due to its GSH-depletion, photothermal efficiency, and tumorspecific properties. [ABSTRACT FROM AUTHOR]

Simple Summary: PARP inhibitors (PARPi) have broad applicability as monotherapy in tumors with HR defects. However, their combination with radiotherapy (RT) is less advanced owing to the rather modest radiosensitization typically achieved with most tested PARPi, including olaparib. Tumor resistance to PARPi or RT is a significant bottleneck in the clinic, and strategically designed combinations of PARPi and RT may offer approaches to overcome such resistance. Talazoparib (BMN673), as compared to other PARPi, is a superior radiosensitizer. In this review, we discuss our evolving understanding of the mechanistic underpinnings of BMN673 radiosensitization and outline the potential for combinations of BMN673 with RT to treat various forms of cancer. BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements. [ABSTRACT FROM AUTHOR]

Simple Summary: Hyperthermia boosts the effects of radio- and chemotherapy regimens, but its clinical potential is hindered by the ability of (cancer) cells to activate a protective mechanism known as the heat stress response. Strategies that inhibit its activation or functions have the potential, therefore, to improve the overall efficacy of hyperthermia-based treatments. In this study, we evaluated the efficacy of the HSP90 inhibitor ganetespib in promoting the effects of radiotherapy or cisplatin combined with hyperthermia in vitro and in a cervix cancer mouse model. Hyperthermia is being used as a radio- and chemotherapy sensitizer for a growing range of tumor subtypes in the clinic. Its potential is limited, however, by the ability of cancer cells to activate a protective mechanism known as the heat stress response (HSR). The HSR is marked by the rapid overexpression of molecular chaperones, and recent advances in drug development make their inhibition an attractive option to improve the efficacy of hyperthermia-based therapies. Our previous in vitro work showed that a single, short co-treatment with a HSR (HSP90) inhibitor ganetespib prolongs and potentiates the effects of hyperthermia on DNA repair, enhances hyperthermic sensitization to radio- and chemotherapeutic agents, and reduces thermotolerance. In the current study, we first validated these results using an extended panel of cell lines and more robust methodology. Next, we examined the effects of hyperthermia and ganetespib on global proteome changes. Finally, we evaluated the potential of ganetespib to boost the efficacy of thermo-chemotherapy and thermo-radiotherapy in a xenograft murine model of cervix cancer. Our results revealed new insights into the effects of HSR inhibition on cellular responses to heat and show that ganetespib could be employed to increase the efficacy of hyperthermia when combined with radiation. [ABSTRACT FROM AUTHOR]

Uncovering radiation toxicity is critical for the adaptation and expansion of advanced radiation therapies and for the development of novel cancer radiotherapy. In the near future, advanced radiotherapies, including heavy ion beam treatment, are expected to be applied in the treatment of dogs, but further basic research on the effects of radiation using canine normal and cancer cells is necessary to actually apply these techniques and achieve high therapeutic efficacy. The radiation sensitivity is varied by the activities of DNA damage response (DDR) and DNA repair. The development of radiosensitizers that target DDR- and DNA repair-kinases, like ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK), is progressing and is expected to be introduced into canine radiotherapy. However, there are no cytotoxicity reports on using the combination of radiation and these sensitizers as treatment in canine cells. In this study, we examined the cytotoxic effects of X-rays and/or radiosensitizers on the Madin–Darby canine kidney (MDCK) cell line. Our results show that X-rays suppress MDCK cell colony formation and proliferation in a dose-dependent manner. Additionally, our observations imply that the combination treatment with ATM inhibitor KU-55933 and DNA-PK inhibitor NU7441 significantly increased X-ray cytotoxicity in MDCK cells compared with the drugs alone. Furthermore, our findings further suggest that MDCK cells might be useful in clarifying the cytotoxicity in canine epithelial cells due to radiation and/or radiosensitizers, such as molecule-targeted drugs. [ABSTRACT FROM AUTHOR]

Investigation of natural products is an attractive strategy to identify novel compounds for cancer prevention and treatment. Numerous studies have shown the efficacy and safety of natural products, and they have been widely used as alternative treatments for a wide range of illnesses, including cancers. However, it remains unknown whether natural products affect homologous recombination (HR)-mediated DNA repair and whether these compounds can be used as sensitizers with minimal toxicity to improve patients' responses to radiation therapy, a mainstay of treatment for many human cancers. In this study, in order to systematically identify natural products with an inhibitory effect on HR repair, we developed a high-throughput image-based HR repair screening assay and screened a chemical library containing natural products. Among the most interesting of the candidate compounds identified from the screen was β-thujaplicin, a bioactive compound isolated from the heart wood of plants in the Cupressaceae family, can significantly inhibit HR repair. We further demonstrated that β-thujaplicin inhibits HR repair by reducing the recruitment of a key HR repair protein, Rad51, to DNA double-strand breaks. More importantly, our results showed that β-thujaplicin can radiosensitize cancer cells. Additionally, β-thujaplicin sensitizes cancer cells to PARP inhibitor in different cancer cell lines. Collectively, our findings for the first time identify natural compound β-thujaplicin, which has a good biosafety profile, as a novel HR repair inhibitor with great potential to be translated into clinical applications as a sensitizer to DNA-damage-inducing treatment such as radiation and PARP inhibitor. In addition, our study provides proof of the principle that our robust high-throughput functional HR repair assay can be used for a large-scale screening system to identify novel natural products that regulate DNA repair and cellular responses to DNA damage-inducing treatments such as radiation therapy.

Simple Summary: Various types of metallic nanoparticles and especially gold nanoparticles (AuNPs) have been utilized in radiation studies to enhance the radiosensitization of cancer cells while minimizing detrimental effects in normal tissue. The aim of our study was to investigate the biological responses of various human cancer cells to gold-nanoparticle-induced radiosensitization. This was accomplished by using different AuNPs and several techniques in order to provide valuable insights regarding the multiple adverse biological effects, following ionizing radiation (IR) in combination with AuNPs. Insightful methodologies such as transmission electron microscopy were employed to identify comprehensively the complexity of the biological damage occurrence. Our findings confirm that AuNP radiosensitization may occur due to extensive and/or complex DNA damage, cell death, or cellular senescence. This multiparameter study aims to further elucidate the biological mechanisms and at the same time provide new information regarding the use of AuNPs as radiosensitizers in cancer treatment. In the context of improving radiation therapy, high-atomic number (Z) metallic nanoparticles and, more importantly, gold-based nanostructures are developed as radiation enhancers/radiosensitizers. Due to the diversity of cell lines, nanoparticles, as well as radiation types or doses, the resulting biological effects may differ and remain obscure. In this multiparameter study, we aim to shed light on these effects and investigate them further by employing X-irradiation and three human cancer cell lines (PC3, A549, and U2OS cells) treated by multiple techniques. TEM experiments on PC3 cells showed that citrate-capped AuNPs were found to be located mostly in membranous structures/vesicles or autophagosomes, but also, in the case of PEG-capped AuNPs, inside the nucleus as well. The colony-forming capability of cancer cells radiosensitized by AuNPs decreased significantly and the DNA damage detected by cytogenetics, γH2AX immunostaining, and by single (γH2AX) or double (γH2AX and OGG1) immunolocalization via transmission electron microscopy (TEM) was in many cases higher and/or persistent after combination with AuNPs than upon individual exposure to ionizing radiation (IR). Moreover, different cell cycle distribution was evident in PC3 but not A549 cells after treatment with AuNPs and/or irradiation. Finally, cellular senescence was investigated by using a newly established staining procedure for lipofuscin, based on a Sudan Black-B analogue (GL13) which showed that based on the AuNPs' concentration, an increased number of senescent cells might be observed after exposure to IR. Even though different cell lines or different types and concentrations of AuNPs may alter the levels of radiosensitization, our results imply that the complexity of damage might also be an important factor of AuNP-induced radiosensitization. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the result of hyperbaric oxygen therapy (HBOT) in women with treated gynaecological malignancies who suffer from late radiation-induced tissue toxicity (LRITT). Moreover, which symptoms of LRITT benefit most from HBOT was evaluated as well.Material and Methods: An online literature search was conducted using PubMed; Embase and the Cochrane Library. Studies were included if the study examined gynaecological cancer patients who had been treated with radiotherapy, who suffered from LRITT and who subsequently received HBOT. In addition, the outcome measures were based on examining the effects of HBOT.Results: Twenty-one articles were included. The study investigating proctitis reported an improvement and three out of four studies investigating cystitis reported decreased complaints in women treated for gynaecological malignancies. In addition, all studies reported improvement in patients with wound complications and fifty percent of the studies reported better Patient Reported Outcome Measurements (PROMS) in women with gynaecological malignancies. Finally, all studies, except one related to pelvic malignancies reported reduced prevalence of symptoms for cystitis and proctitis and all studies reported better PROMS. However, only eleven studies reported p-values, nine of which were significant.Conclusion: This study demonstrated that HBOT has a positive effect in women with gynaecological LRITT. Within the included patient group, gynaecological cancer patients with wound complications seem to benefit most from this treatment compared to other late side effects of LRITT. [ABSTRACT FROM AUTHOR]

Simple Summary: The DNA damage response pathway plays a critical role in maintaining genomic integrity. Therefore, inhibition of activation of cell-cycle checkpoints involved in this pathway may increase the sensitivity of tumor cells to DNA damage induced by ionizing radiation. In this review, we provide an overview of mechanisms, preclinical studies and advances in clinical trials of DNA-PKcs, ATM/ATR, CHK1/CHK2, WEE1 and PARP1 kinase inhibitors combined with radiotherapy for colorectal cancer treatment. We evaluate the potential of developing high-efficiency and low-toxicity radiosensitizers targeting the DNA damage response and DNA repair pathways to enhance the response to radiotherapy in colorectal cancer. Radiotherapy is an important component of current treatment options for colorectal cancer (CRC). It is either applied as neoadjuvant radiotherapy to improve local disease control in rectal cancers or for the treatment of localized metastatic lesions of CRC. DNA double-strand breaks (DSBs) are the major critical lesions contributing to ionizing radiation (IR)-induced cell death. However, CRC stem cells promote radioresistance and tumor cell survival through activating cell-cycle checkpoints to trigger the DNA damage response (DDR) and DNA repair after exposure to IR. A promising strategy to overcome radioresistance is to target the DDR and DNA repair pathways with drugs that inhibit activated cell-cycle checkpoint proteins, thereby improving the sensitivity of CRC cells to radiotherapy. In this review, we focus on the preclinical studies and advances in clinical trials of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related kinase (ATR), checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2), WEE1 and poly (ADP-ribose) polymerase 1 (PARP1) kinase inhibitors in CRC. Importantly, we also discuss the selective radiosensitization of CRC cells provided by synthetic lethality of these inhibitors and the potential for widening the therapeutic window by targeting the DDR and DNA repair pathways in combination with radiotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with curable head and neck cancers are usually treated with a combination of chemotherapy and radiotherapy, but they experience significant, severe side effects, which greatly affect their quality of life. Some of these patients still experience disease relapse after an intensive course of treatment due to tumours that are resistant to radiotherapy and chemotherapy because of hypoxia (lack of oxygen). In addition, some patients are not suitable for and/or are not able to have combined chemotherapy with radiotherapy due to their age or other physical conditions. Certain small-molecule drugs, which are used to treat various infections including malaria, have been shown to reduce hypoxia and thus make radiotherapy more effective. Therefore, their combination with radiotherapy could have less toxicities compared with the combination of chemotherapy with radiotherapy. Here, we discuss the promising results from preclinical work and clinical trials of these agents, and their potential use in the clinic, to reduce hypoxia and to sensitise radiotherapy. These agents could potentially be used for patients who are not suitable for combined chemotherapy and radiotherapy; they may also be used to reduce the dose of radiotherapy if able to enhance radiotherapy effect at lower dose in order to reduce toxicities while maintaining the treatment efficacy in a more personalised manner. The addition of platinum chemotherapy to primary radiotherapy (chemoradiation) improves survival outcomes for patients with head and neck squamous cell carcinoma (HNSCC), but it carries a high incidence of acute and long-term treatment-related complications, resulting in a poor quality of life. In addition, patients with significant co-morbidities, or older patients, cannot tolerate or do not benefit from concurrent chemoradiation. These patients are often treated with radiotherapy alone resulting in poor locoregional control and worse survival outcomes. Thus, there is an urgent need to assess other less toxic treatment modalities, which could become an alternative to chemoradiation in HNSCC. Currently, there are several promising anti-cancer drugs available, but there has been very limited success so far in replacing concurrent chemoradiation due to their low efficacy or increased toxicities. However, there is new hope that a treatment strategy that incorporates agents that act as radiosensitisers to improve the efficacy of conventional radiotherapy could be an alternative to more toxic chemotherapeutic agents. Recently, imidazole-based or quinone-based anti-malarial compounds have drawn considerable attention as potential radiosensitisers in several cancers. Here, we will discuss the possibility of using these compounds as radiosensitisers, which could be assessed as safe and effective alternatives to chemotherapy, particularly for patients with HNSCC that are not suitable for concurrent chemotherapy due to their age or co-morbidities or in metastatic settings. In addition, these agents could also be tested to assess their efficacy in combination with immunotherapy in recurrent and metastatic settings or in combination with radiotherapy and immunotherapy in curative settings. [ABSTRACT FROM AUTHOR]

Radiotherapy is an established therapy in cancer treatments that uses energy deposition directly into tumor tissue. With the introduction of radiosensitizers, invasive surgical and chemotherapy techniques can be avoided. Radiosensitizers with a high-Z base such as gold nanoparticles (AuNPs) are promising candidates for catalyzing tumor injury and simultaneously enabling tracking to be done inside the organ via a computed tomography scan or other diagnostic imaging. It has been documented that AuNP possess biocompatibility characteristics as well as nontoxic properties depending on the size of the application and the applied coating. Radiosensitizers can increase tumor targeting, thus providing more specific destruction than conventional techniques while minimizing damage to surrounding healthy tissues. This review focuses on the special properties of AuNP in assisting radiotherapy as a radiosensitizing agent. Important parameters for AuNP's optimization are listed to offer general guidelines for which the specifications of AuNP should be directed. In addition, the mechanism of AuNP radiosensitization in physical, chemical, and biological phases is discussed. A list of in vitro and in vivo testing and current clinical trials of AuNP are presented in sequence. Finally, the utilization of AuNP for diagnosing and combating the COVID-19 pandemic is discussed for future outbreak surveillance and intervention. [ABSTRACT FROM AUTHOR]

Purpose: Radiotherapy is one of the most important therapeutic options used to treat cancers. Radiation effects can be improved using nanoparticles and chemotherapeutic drugs as radiosensitizing agents. The aim of the present study was to evaluate the effects of folic acidconjugated gold nanoparticles (GNP-F) in combination with doxorubicin (DOX) and x-Ray irradiation in colorectal cancer (CRC) cell line (HT-29). Methods: The cell viability assay (WST-1) was performed to study the cytotoxic effects of different concentrations of DOX and GNP-F after 24 and 48 hours treatments. Then, the effects of the GNP-F, X-Ray irradiation, and DOX drug in single and combined treatments were examined after 24 and 48 hours treatment with effective doses. Likewise, the caspase 3 gene expression ratio and the caspase 3 activity were assessed after 48 h treatment. Moreover, the malondialdehyde (MDA) level was determined in treated and untreated cells. Results: When GNP-F (at a concentration of 70 μM) was combined with X-ray irradiation (2 Gy) and DOX drug, induced more cytotoxic effects compared to the control group. The results of cell viability assay showed that GNP-F + X-Ray in combination with a low concentration of DOX (0.25 x IC50) enhanced the cytotoxic effects of cells compared to related single treatments. Caspase 3 gene expression ratio and caspase 3 activity increased in double and triple combination treatments in comparison with the single groups. Moreover, the MDA level increased in triple combination compared to the single treatments. Conclusion: Our findings confirmed the potential anti-cancer effects of the GNP-F and DOX in combination with X-Ray irradiation in CRC cells. [ABSTRACT FROM AUTHOR]

Objective. To investigate the influence of dehydroxymethylepoxyquinomicin (DHMEQ), an NF-κB inhibitor, on radiosensitivity of thyroid carcinoma (TC) TPC-1 cells. Methods. The isolation of CDl33 positive cells (CD133+ TPC-1) and negative cells (CD133- TPC-1) from TPC-1 cells used immunomagnetic bead sorting. After verification of the toxicity of DHMEQ to cells by MTT and cell cloning assays, the cells were divided into four groups, of which three groups were intervened by DHMEQ, 131I radiation, and DHMEQ +131I radiation, respectively, while the fourth group was used as a control without treatment. Alterations in cell growth, apoptosis, and cell cycle were observed. Results. DHMEQ had certain toxic effects on TPC-1 cells, with an IC50 of 38.57 μg/mL (P < 0.05). DHMEQ inhibited CD133+ and CD133- TPC-1 proliferation and their clonogenesis after irradiation. DHMEQ + radiation contributed to a growth inhibition rate and an apoptosis rate higher than either or them alone (P < 0.05), with a more significant effect on CD133- TPC-1 than CD133+ TPC-1 under the same treatment conditions (P < 0.05). Conclusion. DHEMQ can increase the radiosensitivity of TC cells to 131I, inhibit tumor cell growth, and promote apoptosis. However, its effect is less significant on CD133+ TPC-1 compared with CD133- TPC-1, which may be related to the stem cell-like properties of CD133+ cells. In the future, the application of DHMEQ in TC 131I radiotherapy will effectively improve the clinical effect of patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Radiotherapy (RT) controls HCC unsatisfactorily and temporarily. Histone deacetylase inhibitor (HDACi) is a heterogeneous group of epigenetic therapeutics with promising anticancer effects and synergism in combination with RT. HDACi modulates natural killer (NK) cell ligand expression on tumor cells, and leads to immune evasion of cancer cells. Expressions of NK group 2D (NKG2D) ligands on cancer cells determine the cytotoxic effect by interacting with NKG2D receptor on NK cells. However, the role of NKG2D signaling in HCC upon combined RT and HDACi remains unclear. Method: In vitro co-culture system with NK cells was tested for human and murine HCC cell lines. Pan-HDACi (panobinostat) and specific HDAC4 knockdown (HDAC4-KD) were used for HDAC inhibition. Clonogenic assay and flow cytometry examined HCC cell survival and NKG2D ligand expression, respectively. Syngeneic mouse model was used to validate the radiosensitizing effect in vivo. Results: Combined RT and HDACi/HDAC4-KD significantly enhanced NK cellrelated cytotoxicity and increased NKG2D ligands, MICA/MICB expressions in human and RAE-1/H60 expressions in murine HCC cells. Delayed tumor growth in vivo by the combinational treatment of RT and HDACi/HDAC4-KD was shown with the associated NKG2D ligand expressions. However, NKG2D receptor did not significantly change among tumors. Conclusion: Radiosensitizing effect with combined RT and HDAC inhibition increased the expression of NKG2D ligands in HCC cells and enhanced their susceptibility to NK cell-mediated cytotoxicity. These findings imply the potential use of combined RT/HDACi and NK cell-directed immunotherapy. [ABSTRACT FROM AUTHOR]

Radioresistance towards radiation therapy has generated the need for the development of radiosensitizers as a potential drug. KRAS mutation brings radioresistance in tumor cells. The present work proves sensitization of cancer cells towards radiotherapy through inhibition of KRAS activation. Acquiring a drug repurposing approach, the in-silico screening revealed that pixantrone, an antineoplastic drug, possesses a high affinity towards KRAS G12C and G12D subtypes. The SPR study suggests that maximum affinity of pixantrone was observed with KRAS G12C>WT>G12D and G12S. Pixantrone potentially inhibited the KRAS activation in stable transfectants G12C and G12D cell lines and radiosensitized distinct KRAS mutant subtype cells. The combination of pixantrone with radiation causes enhanced dsDNA breaks along with enhanced ATM expression, and increased late apoptosis. The preclinical studies on NCr-fox1nu xenograft mice showed potent inhibition of tumor progression and prolonged survival of mcie due to the radiosensitizing effect of pixantrone. Radiation-induced activation of key effector proteins of RAS downstream pathways, like MAPK and PI3K/Akt/mTOR pathways, were downregulated in tumor cells upon combination treatment. Interestingly, a robust upregulation of senescence marker p21 was observed in the tumor cells in combination treatment. These findings reveal a convergence between KRAS signaling, pixantrone treatment, and radiation conferring tumor cell death. [Display omitted] • Oncogenic KRAS causes radioresistance in tumor cells. • Pixantrone inhibits mutant KRAS and radiosensitizes cancer cells. • Radiation treatment upregulates MAPK and PI3K/Akt prosurvival pathway proteins in xenograft model. • Pixantrone in combination with radiation causes suppression of prosurvival pathway proteins, inhibiting tumor growth. [ABSTRACT FROM AUTHOR]

Purpose: In the current study, we aimed to look into the macroscopic and microscopic dose enhancement effect of metallic nanoparticles in interstitial brachytherapy of gastric adenocarcinoma by Iodine-125 source using a nano-lattice model in MCNPX (2.7) and MCNP6.1 codes. Materials and methods: Based on a nano-lattice simulation model containing a radiation source and a tumor tissue with cellular compartments loaded with 7 mg/g spherical nanoparticles, the microscopic and macroscopic levels of energy deposition by the secondary electrons was estimated. Results: The results show that the values of macroscopic DEF are higher than microscopic DEF values and the macroscopic DEF values decrease by increasing the distance from the surface of brachytherapy source. Accordingly, it could be noted that gold nanoparticles have the highest radiosensitization effect among the other nanoparticles and the related DEF value is close to the resultant DEF values for bismuth nanoparticles. Moreover, the results revealed a remarkable discrepancy between the DEF and secondary electron spectra calculated by MCNPX (2.7) and MCNP6.1 codes, which could be justified by the difference in energy cut-off and electron transport algorithms of two codes. Conclusions: According to the both MCNPX (2.7) and MCNP6.1 outputs, it could be concluded that the presence of metallic nanoparticles in the tumor tissue of gastric adenocarcinoma increases the physical effectiveness of brachytherapy by I-125 source. This study aims to provide recommendations for future preclinical studies. Actually, the results presented herein give a physical view of radiosensitization potential of different metallic nanoparticles and could be considered in design of analytical and experimental radiosensitization studies in tumor regions using various radiotherapy modalities in the presence of heavy nanomaterials. [ABSTRACT FROM AUTHOR]

We report on the low energy anion spectra of 5-cyanateuracil (5-OCNU) and 5-thiocyanateouracil (5-SCNU), which have been the suggested potential radiosensitizers for use in cancer therapy [L. Chomicz et al., J. Phys. Chem. Lett. 4, 2853-2857 (2013)]. Employing bound state and scattering calculations, we obtained, for both molecules, a dipole bound state, a π* valence bound state, and four π* resonances, besides a σ* SCN resonance for 5-SCNU. The cyanate and thiocyanate substituents give rise to additional long-lived π* resonances, compared to 5-halouracil radiosensitizers. From the reaction thresholds and the expected vibronic couplings among the anion states, efficient production of SCN and CN anions and radical fragments should be observed in dissociative electron attachment measurements for 5-SCNU. The corresponding dissociation processes in 5-OCNU are expected to be less effective in view of the lack of a long-lived σ* OCN shape resonance and the little σ* admixture into the π* resonances located on the cyanate group. The present results thus indicate 5-SCNU as a more promising radiosensitizer at sub-excitation energies. [ABSTRACT FROM AUTHOR]

The limited efficacy of radiotherapy leads to radio‐resistance and high rates of tumor recurrence and metastasis, which is caused by tumor hypoxia, rapid DNA damage repair, and especially the suppressive immune microenvironment of tumor. Lots of immune cell‐derived exosomes can regulate antitumor immunity, but their application in enhancing radiotherapy is rarely studied. Herein, as a model of concept, M1 macrophage‐derived exosomes (M1Exos) is engineered as effective radiotherapy sensitizers, realizing the trilogy of radiotherapy sensitization: 1) M1Exos is engineered to express catalases on the inside of membrane, which can effectively relieve tumor hypoxia, and enhance DNA damage. 2) The DNA damage repair inhibitor is loaded in M1Exos to effectively inhibit DNA damage repair. 3) M1Exos can polarize M2 macrophages into M1 phenotypes, and the anti‐PD‐L1 nanobody engineered on the outside of M1Exos can relieve the immunosuppression of T cells, both ultimately leading to the remodeling of the tumor suppressive microenvironment. The trilogy of radiotherapy sensitization achieves excellent antitumor efficacy, exhibiting the good utility of engineering immune cell‐derived exosomes as radiotherapy sensitizers, inspiring the future efforts to explore different kinds of immune cell‐derived exosomes for enhanced radiotherapy. [ABSTRACT FROM AUTHOR]

KP167 is a novel hypoxia‐activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU‐55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER0.01 of 1.60–3.42). KP167 induced greater radiosensitization in TNBC (SER0.01 2.53 in MDAMB‐231, 2.28 in MDAMB‐468, 4.55 in MDAMB‐436) and luminal spheroids (SER0.01 1.46 in MCF‐7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER0.01 of 1.56–2.37 compared with AQ4N SER0.01 of 1.13–1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Nanoparticle treatment on tumor cells is proposed for its potential radiosensitizing properties, increasing the radiation effect on tumor cells and reducing the adverse effects on healthy tissues. The present study evaluates, on two cell lines derived from colon and breast adenocarcinomas, the impact of irradiation in the presence of specifically targeted gold nanoparticles. Cells were irradiated in the absence and in the presence of non-functionalized or specifically functionalized gold nanoparticles. The results pointed out that actively targeting gold nanoparticles has a clear radiosensitizing effect in both cell lines. Radiation therapy is widely used as an anti-neoplastic treatment despite the adverse effects it can cause in non-tumoral tissues. Radiosensitizing agents, which can increase the effect of radiation in tumor cells, such as gold nanoparticles (GNPs), have been described. To evaluate the radiosensitizing effect of 50 nm GNPs, we carried out a series of studies in two neoplastic cell lines, Caco2 (colon adenocarcinoma) and SKBR3 (breast adenocarcinoma), qualitatively evaluating the internalization of the particles, determining with immunofluorescence the number of γ-H2AX foci after irradiation with ionizing radiation (3 Gy) and evaluating the viability rate of both cell lines after treatment by means of an MTT assay. Nanoparticle internalization varied between cell lines, though they both showed higher internalization degrees for functionalized GNPs. The γ-H2AX foci counts for the different times analyzed showed remarkable differences between cell lines, although they were always significantly higher for functionalized GNPs in both lines. Regarding cell viability, in most cases a statistically significant decreasing tendency was observed when treated with GNPs, especially those that were functionalized. Our results led us to conclude that, while 50 nm GNPs induce a clear radiosensitizing effect, it is highly difficult to describe the magnitude of this effect as universal because of the heterogeneity found between cell lines. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the major causes of cancer-related deaths worldwide, primarily because of the limitations of conventional clinical therapies such as chemotherapy and radiation therapy. Side effects associated with these treatments have made it essential for new modalities, such as tumor targeting nanoparticles that can provide cancer specific therapies. In this research, we have developed novel dual-stimuli nanoparticles (E-DSNPs), comprised of two parts; (1) Core: responsive to glutathione as stimuli and encapsulating Cisplatin (a chemo-drug), and (2) Shell: responsive to irradiation as stimuli and containing NU7441 (a radiation sensitizer). The targeting moieties on these nanoparticles are Ephrin transmembrane receptors A2 (EphA2) that are highly expressed on the surfaces of lung cancer cells. These nanoparticles were then evaluated for their enhanced targeting and therapeutic efficiency against lung cancer cell lines. E-DSNPs displayed very high uptake by lung cancer cells compared to healthy lung epithelial cells. These nanoparticles also demonstrated a triggered release of both drugs against respective stimuli and a subsequent reduction in in vitro cancer cell survival fraction compared to free drugs of equivalent concentration (survival fraction of about 0.019 and 0.19, respectively). Thus, these nanoparticles could potentially pave the path to targeted cancer therapy, while overcoming the side effects of conventional clinical therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: DNA damage response (DDR) inhibitors have been shown to sensitize cells to radiation yet have seen limited application in clinical settings. This could be due to a lack of understanding of how these inhibitors interact with ionizing radiation (IR) dose fractionation and cellular repair. Our study investigated the radiosensitizing effect of different DDR inhibitors on human breast cancer cells, utilizing single-dose and fractionated IR. Their effect on damage repair, DNA double-strand break repair kinetics and cell cycle distribution was also evaluated. The main finding was that radiosensitization by DDR inhibition was more prominent when combined with fractionated IR than single-dose IR. Moreover, DDR inhibition impeded the repair of IR-induced DNA double-strand breaks. Altogether, our study established the radiosensitizing potential of DDR inhibitors while highlighting the importance of IR dose fractionation in similar studies. Pharmacological inhibitors of DNA damage response (DDR) proteins, such as the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases and poly (ADP-ribose) polymerase (PARP), have been developed to overcome tumor radioresistance. Despite demonstrating radiosensitization preclinically, they have performed suboptimally in clinical trials, possibly due to an incomplete understanding of the influence of DDR inhibition on ionizing radiation (IR) dose fractionation and sublethal damage repair. Hence, this study aimed to evaluate the radiosensitizing ability under fractionation of ATM inhibitor AZD0156, ATR inhibitor AZD6738 and PARP inhibitor AZD2281 (olaparib), utilizing MDA-MB-231 and MCF-7 human breast cancer cells. Clonogenic assays were performed to assess cell survival and sublethal damage repair after treatment with DDR inhibitors and either single-dose or fractionated IR. Immunofluorescence microscopy was utilized to evaluate DNA double-strand break repair kinetics. Cell cycle distributions were investigated using flow cytometry. All inhibitors showed significant radiosensitization, which was significantly greater following fractionated IR than single-dose IR. They also led to more unrepaired DNA double-strand breaks at 24 h post-IR. This study provides preclinical evidence for the role of AZD0156, AZD6738 and olaparib as radiosensitizing agents. Still, it highlights the need to evaluate these drugs in fractionated settings mirroring clinical practice to optimize the trial design. [ABSTRACT FROM AUTHOR]

Background: Resistance to radiotherapy is a common cause of treatment failure in advanced head and neck squamous cell carcinoma (HNSCC). ß-Thujaplicin, a natural tropolone derivative, acts as an anti-cancer agent and has recently been shown to radiosensitize non-HNSCC cancer cells. However, no data is currently available on its radiosensitizing potential in HNSCC. Methods: To investigate the effect of ß-Thujaplicin and irradiation in HNSCC cell lines CAL27 and FADU, we performed a cell viability assay, colony forming assay, flow cytometry for cell cycle analysis and a wound healing assay. Drug-irradiation interaction was analyzed using a zero-interaction potency model. Results: Treatment with ß-Thujaplicin led to a dose-dependent decrease in cell viability and enhanced the effect of irradiation. Clonogenic survival was inhibited with synergistic drug-irradiation interaction. ß-Thujaplicin further led to S-phase arrest and increased the sub-G1 population. Moreover, combined ß-Thujaplicin and irradiation treatment had a higher anti-migratory effect compared to irradiation alone. Conclusions: ß-Thujaplicin acts as a radiosensitizer in HNSCC cell lines. Further evaluation of its use in HNSCC therapy is warranted. [ABSTRACT FROM AUTHOR]

The long non-coding RNA (lncRNA) PVT1 was first found to activate variant translocations in the plasmacytoma of mice. Human lncPVT1 is located on chromosome 8q24.21, at the same locus as the well-known MYC oncogene. LncPVT1 has been found to promote the progression of various malignancies. Chemoresistance and radioresistance seriously affect tumor treatment efficacy and are associated with the dysregulation of physiological processes in cancer cells, including apoptosis, autophagy, stemness (for cancer stem cells, CSC), hypoxia, epithelial-mesenchymal transition (EMT), and DNA damage repair. Previous studies have also implicated lncPVT1 in the regulation of these physiological mechanisms. In recent years, lncPVT1 was found to modulate chemoresistance and radioresistance in some cancers. In this review, we discuss the mechanisms of lncPVT1-mediated regulation of cellular chemoresistance and radioresistance. Due to its high expression in malignant tumors and sensitization effect in chemotherapy and radiotherapy, lncPVT1 is expected to become an effective antitumor target and chemotherapy and radiotherapy sensitizer, which requires further study. [ABSTRACT FROM AUTHOR]

Catalytic radiosensitization opens up a new promising direction of radiotherapy enhancement from the perspective of catalytic chemistry, and also provides more opportunities for the design and application of biomedical catalytic materials. This review summarizes the ingenious design and application of catalytic nanomaterials in tumor catalytic radiosensitization from the aspects of electron modulation and energy conversion, respectively, and proposes the strategies, challenges and guidelines for the further development of the catalytic radiosensitization. [Display omitted] Radiotherapy is indispensable in clinical cancer treatment, but because both tumor and normal tissues have similar sensitivity to X-rays, their clinical curative effect is intrinsically limited. Advanced nanomaterials and nanotechnologies have been developed for radiotherapy sensitization, typically employing high atomic number (high-Z) materials to enhance the energy deposition of X-rays in tumor tissues, but the efficiency is largely limited by the toxicity of heavy metals. A new and promising approach for radiosensitization is catalytic radiosensitization, which takes advantage of the catalytic activity of nanomaterials triggered by radiation. The efficiency of catalytic radiosensitization can be greatly enhanced by electron modulation and energy conversion of nanocatalysts upon X-ray irradiation, further enhancing the clinical curative effect. In this review, we highlight the challenges and opportunities in cancer radiosensitization, discuss novel approaches to catalytic radiosensitization, and finally describe the development of catalytic radiosensitization based on an in-depth understanding of radio-nano interactions and catalysis–biological interactions. [ABSTRACT FROM AUTHOR]

The processes in 2–128 nm iron nanoparticles (NP) under 10–800 Ry photon irradiation are studied by detailed Monte Carlo simulations, accounting for the cascade decays of inner-shell vacancies. The cascade decay of vacancies is a crucial factor in the theoretical description of the effect of ionizing radiation on matter. The NPs re-emit most of the energy of an absorbed photon into the surrounding medium with secondary electrons and photons emitted by NP. At incident photon energies under the Fe1s-ionization threshold, most of the energy is carried away by electrons; when photon energy is above the Fe1s-threshold, electrons and photons transfer the energy to the surrounding medium. In the case of large nanoparticles, many low-energy electrons are emitted by NP, over a hundred per one initial photon. Although the energy carried away by them is small, they contribute to forming a high positive charge on the NP, which results in great electric fields near the NP surface. The significance of the NP electric field effect on the DNA repair cycle is discussed. [ABSTRACT FROM AUTHOR]

Chemo-radiotherapy is one of the promising approaches to treat bladder cancer, but its effectiveness is limited to sensitive patients. Polyphenol curcumin has shown anticancer and radiosensitizing potentials, but the mechanism is not fully understood. Here, the In Vitro response of UM-UC5 and UM-UC6 bladder cell lines to curcumin and radiation treatments was evaluated. The effect of curcumin on the DNA double-strand breaks repair system after treatment with ionizing radiation (2 Gy) was determined by immunofluorescence. Cell viability, proliferation, and survival were performed using trypan blue, MTT, clonogenic, and sphere-forming assays. The migratory ability of both cells was assessed by wound healing. We showed that curcumin treatment increased the radiosensitivity by modifying the DNA double-strand breaks repair kinetics of the most radioresistant cells UM-UC6 without affecting the radiosensitive UM-UC5. Moreover, UM-UC6 cell survival and proliferation was significantly decreased after the combination of curcumin with radiation. Bladder cell migration was also inhibited considerably. Curcumin was also shown to reduce the number and the volume of bladder cancer spheres of both cell lines. This study revealed that curcumin was able to radiosensitize resistant bladder cell line without affecting the sensitive one with minimal side effects through enhancing DNA damage signaling and repair pathway. [ABSTRACT FROM AUTHOR]

Radiation therapy is one of the most commonly used methods in clinical cancer treatment, and radiosensitizers could achieve enhanced therapeutic efficacy by incorporating heavy elements into structures. However, the secondary excitation of these high-Z elements-doped nanosensitizers still imply intrinsic defects of low efficiency. Herein, we designed Bi-doped titanium dioxide nanosensitizers in which high-Z Bi ions with adjustable valence state (Bi3+ or Bi4+) replaced some positions of Ti4+ of anatase TiO2, increasing both X-rays absorption and oxygen vacancies. The as-prepared TiO2:Bi nanosensitizers indicated high ionizing radiation energy-transfer efficiency and photocatalytic activity, resulting in efficient electron–hole pair separation and reactive oxygen species production. After further modification with cancer cell targeting peptide, the obtained nanoplatform demonstrated good performance in U87MG cell uptakes and intracellular radicals-generation, severely damaging the vital subcellular organs of U87MG cells, such as mitochondrion, membrane lipid, and nuclei etc. These combined therapeutic actions mediated by the composition-tunable nanosensitizers significantly inhibited the U87MG tumor growth, providing a refreshing strategy for X-ray induced dynamic therapy of malignant tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: The occurrence of severe normal tissue side effects and acquired drug resistance of the malignancy are the most important limitations that are associated with currently given systemic treatment in pancreatic cancer. The aim of this study was to assess the therapeutic efficacy of encapsulated cisplatin prodrug and gold nanoparticles combined with radiation to improve the toxicity profile of cisplatin and develop new multimodality treatments. Here, we demonstrated the therapeutic effect of NAs-cisPt as a platform to encourage nanomedicine in the context for future applications in multimodality treatments. Considering the dismal survival rate, novel therapeutic strategies are warranted to improve the outcome of pancreatic ductal adenocarcinoma (PDAC). Combining nanotechnology for delivery of chemotherapeutics—preferably radiosensitizing agents—is a promising approach to enhance the therapeutic efficacy of chemoradiation. We assessed the effect of biodegradable ultrasmall-in-nano architectures (NAs) containing gold ultra-small nanoparticles (USNPs) enclosed in silica shells loaded with cisplatin prodrug (NAs-cisPt) combined with ionizing radiation (IR). The cytotoxic effects and DNA damage induction were evaluated in PDAC cell lines (MIA PaCa2, SUIT2-028) and primary culture (PDAC3) in vitro and in the chorioallantoic membrane (CAM) in ovo model. Unlike NAs, NAs-cisPt affected the cell viability in MIA PaCa2 and SUIT2-028 cells. Furthermore, NAs-cisPt showed increased γH2AX expression up to 24 h post-IR and reduced β-globin amplifications resulting in apoptosis induction at DNA and protein levels. Similarly, combined treatment of NAs-cisPt + IR in PDAC3 and SUIT2-028 CAM models showed enhanced DNA damage and apoptosis leading to tumor growth delay. Our results demonstrate an increased cytotoxic effect of NAs-cisPt, particularly through its release of the cisplatin prodrug. As cisplatin is a well-known radiosensitizer, administration of cisplatin prodrug in a controlled fashion through encapsulation is a promising new treatment approach which merits further investigation in combination with other radiosensitizing agents. [ABSTRACT FROM AUTHOR]

Radiation therapy against cancer cells often causes radiation resistance via accumulation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) under hypoxic conditions and severe side effects. Radiation sensitizers without side effects are required to overcome hypoxia-induced radiation resistance and decrease radiation-related side effects in patients with refractory cancer. We previously developed oxygen nanobubble water (NBO2 water) and demonstrated that it suppresses hypoxia-induced radiation resistance in cancer cell lines within the single-nanometer range. This study aimed to elucidate whether NBO2 water could act as a radiosensitizer via regulation of HIF-1α in a tumor-bearing mouse model. Six-week-old female BALB/c mice subcutaneously injected with tumor cells received control water or NBO2 water for 28 days, after which biochemical examinations and radiation treatment were performed. Hypoxic tumor regions were detected immunohistochemically. We found that NBO2 water sensitized radiation reactivity in the xenografted tumors. Notably, NBO2 water administration downregulated the accumulation of HIF-1α in xenografted tumors and did not affect the vital organs of healthy mice. The combination of radiation and single-nanometer NBO2 water without severe side effects may be a promising therapeutic option to improve radiation sensitivity in cancer patients without tolerance to invasive treatments. [ABSTRACT FROM AUTHOR]

Radiation concomitant with the DNA methylating drug temozolomide (TMZ) is the gold standard in the treatment of glioblastoma. In this adjuvant setting, TMZ is regarded to be a radiation sensitizer. However, similar to ionising radiation, TMZ induces DNA double-strand breaks and is itself a potent trigger of apoptosis, cellular senescence and autophagy, suggesting that radiation and TMZ act independently. Although cell culture experiments yielded heterogeneous results, some data indicate that the cytotoxic effect of radiation was only enhanced when TMZ was given before radiation treatment. Based on the molecular mechanism of action of TMZ, the importance of specific TMZ and radiation-induced DNA lesions, their repair as well as their interactions, possible scenarios for an additive or synergistic effect of TMZ and radiation are discussed, and suggestions for an optimal timing of radio-chemical treatments are proposed. [ABSTRACT FROM AUTHOR]

In this work, an intercomparison of sensitization effects produced by gold (GNP) and dextran-coated iron oxide (SPION-DX) nanoparticles in M059J and U87 human glioblastoma cells was performed using 6 MV-photons. Three variables were mapped: the nanoparticle material, treatment concentration, and cell radiosensitivity. For U87, GNP treatments resulted in high sensitization enhancement ratios (SER 10 % up to 2.04). More modest effects were induced by SPION-DX, but still significant reductions in survival were achieved (maximum SER 10 % = 1.61 ). For the radiosensitive M059J, sensitization by both NPs was poor. SER 10 % increased with the degree of elemental uptake in the cells, but not necessarily with treatment concentration. For GNP, where exposure concentration and elemental uptake were found to be proportional, SER 10 % increased linearly with concentration in both cell lines. For SPION-DX, saturation of sensitization enhancement and metal uptake occurred at high exposures. Fold change in the α / β ratios extracted from survival curves are reduced by the presence of SPION-DX but strongly increased by GNPs , suggesting that sensitization by GNPs occurs mainly via promotion of lethal damage, while for SPION-DX repairable damage dominates. The NPs were more effective in eliminating the radioresistant glioblastoma cells, an interesting finding, as resistant cells are key targets to improve treatment outcome. [ABSTRACT FROM AUTHOR]

Ionizing radiation activates cytoprotective pathways in cancer cells. Fibroblast growth factor receptor (FGFR) is a key player in these pathways. Thus, FGFR signaling is a potential target to induce radiosensitization. LY2874455 is an orally administrable selective pan-FGFR inhibitor. However, the radiosensitizing effects of LY2874455 remain unclear. In this study, we addressed this issue by using radioresistant human cancer cell lines H1703 (FGFR1 mutant), A549 (FGFR1–4 wild-type), and H1299 (FGFR1–4 wild-type). At an X-ray dose corresponding to 50%-clonogenic survival as the endpoint, 100 nM LY2874455 increased the sensitivity of H1703, A549, and H1299 cells by 31%, 62%, and 53%, respectively. The combination of X-rays and LY2874455 led to a marked induction of mitotic catastrophe, a hallmark of radiation-induced cell death. Furthermore, combination treatment suppressed the growth of A549 xenografts to a significantly greater extent than either X-rays or the drug alone without noticeable toxicity. This is the first report to show the radiosensitizing effect of a selective pan-FGFR inhibitor. These data suggest the potential efficacy of LY2874455 as a radiosensitizer, warranting clinical validation. [ABSTRACT FROM AUTHOR]

This study aims at analyzing the impact of the pharmacological inhibition of DNA damage response (DDR) targets (DNA-PK and ATR) on radiosensitization of bladder cancer cell lines of different molecular/histological subtypes. Applying DNA-PK (AZD7648) and ATR (Ceralasertib) inhibitors on SCaBER, J82 and VMCUB-1 bladder cancer cell lines, we revealed sensitization upon ionizing radiation (IR), i.e., the IC50 for each drug shifted to a lower drug concentration with increased IR doses. In line with this, drug exposure retarded DNA repair after IR-induced DNA damage visualized by a neutral comet assay. Western blot analyses confirmed specific inhibition of targeted DDR pathways in the analyzed bladder cancer cell lines, i.e., drugs blocked DNA-PK phosphorylation at Ser2056 and the ATR downstream mediator CHK1 at Ser317. Interestingly, clonogenic survival assays indicated a cell-line-dependent synergism of combined DDR inhibition upon IR. Calculating combined index (CI) values, with and without IR, according to the Chou–Talalay method, confirmed drug- and IR-dose-specific synergistic CI values. Thus, we provide functional evidence that DNA-PK and ATR inhibitors specifically target corresponding DDR pathways retarding the DNA repair process at nano-molar concentrations. This, in turn, leads to a strong radiosensitizing effect and impairs the survival of bladder cancer cells. [ABSTRACT FROM AUTHOR]

Increased radioresistance due to previous irradiation or radiosensitivity due to human papilloma virus (HPV) infection can be observed in head and neck squamous cell carcinoma (HNSCC). The DNA-damage response of cells after exposure to DNA-damaging agents plays a crucial role in determining the fate of exposed cells. Tightly regulated and interconnected signaling networks are activated to detect, signal the presence of and repair the DNA damage. Novel therapies targeting the DNA-damage response are emerging; however, an improved understanding of the complex signaling networks involved in tumor radioresistance and radiosensitivity is needed. In this study, we exposed isogenic human HNSCC cell lines with altered radiosensitivity to DNA-damaging agents: radiation, cisplatin and bleomycin. We investigated transcriptional alterations in the DNA-damage response by using a pathway-focused panel and reverse-transcription quantitative PCR. In general, the isogenic cell lines with altered radiosensitivity significantly differed from one another in the expression of genes involved in the DNA-damage response. The radiosensitive (HPV-positive) cells showed overall decreases in the expression levels of the studied genes. In parental cells, upregulation of DNA-damage signaling and repair genes was observed following exposure to DNA-damaging agents, especially radiation. In contrast, radioresistant cells exhibited a distinct pattern of gene downregulation after exposure to cisplatin, whereas the levels in parental cells were unchanged. Exposure of radioresistant cells to bleomycin did not significantly affect the expression of DNA-damage signaling and repair genes. Our analysis identified several possible targets: NBN, XRCC3, ATR, GADD45A and XPA. These putative targets should be studied and potentially exploited for sensibilization to ionizing radiation and/or cisplatin in HNSCC. The use of predesigned panels of DNA-damage signaling and repair genes proved to offer a convenient and quick approach to identify possible therapeutic targets. [ABSTRACT FROM AUTHOR]