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The efficacy of radiation treatment (RT) of head and neck squamous cell carcinoma (HNSCC) is limited by radioresistance and the toxicity of FDA approved radiosensitizers. In extension to our previous research where we demonstrated that telaglenastat (CB839) increased efficacy of RT in in vitro and in vivo HNSCC models, here, we examine the radiosensitizing effects of telaglenastat in comparison to cisplatin's, as cisplatin is currently the standard of care for concurrent therapy. Combination of telaglenastat with RT reduced tumor volume in a HNSCC patient derived xenograft mouse model. The efficacy of telaglenastat with RT in reducing cell survival and increasing apoptosis was similar if not greater than that of cisplatin with RT in Cal27 and HN5 HNSCC cells. The addition of telaglenastat increased reactive oxygen species and reduced the antioxidant glutathione in both Cal27 and HN5 cells. Reverse Phase Protein Array analyses revealed alterations in cell death and DNA damage response proteins. This study provides the scientific underpinnings for the use of telaglenastat as a radiosensitizer in the treatment of HNSCC either as an alternative to cisplatin or in cisplatin-ineligible patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: The radiation sensitivity of tumor cells is a critical determinant of their therapeutic response to radiotherapy. Histone deacetylase 6 (HDAC6), beyond its known role in modulating tubulin acetylation and influencing cell motility, is also involved in the DNA damage response, potentially enhancing tumor cell radiosensitivity. Targeted HDAC6 inhibitors have shown substantial promise in preclinical studies aimed at increasing radiosensitivity and inhibiting cellular migration., Methods: A new HDAC inhibitor, named OXHA, was designed by substituting the phenyl cap of SAHA with an N,5-diphenyloxazole-2-carboxamide group. The inhibitory activity of OXHA was evaluated via in vitro enzymatic assays. Its effects on tumor cell migration and radiosensitization potential were assessed using scratch wound healing assays, micronucleus formation, and clonogenic survival assays., Result: Enzymatic assays confirmed OXHA's selective inhibition of HDAC6. Compared to SAHA, OXHA significantly increased α-tubulin acetylation while minimally impacting histone H3 acetylation, indicating a high selectivity for HDAC6. In combination with X-ray irradiation, OXHA markedly impaired wound healing in A549 and HepG2 cells, enhanced micronucleus formation, and reduced clonogenic survival across multiple tumor lines., Conclusion: OXHA exhibits potent and selective HDAC6 inhibition, effectively impeding tumor cell migration and enhancing radiosensitivity across multiple cell lines. These findings suggest that OXHA has strong potential as a therapeutic strategy to improve radiotherapy efficacy., Competing Interests: Declarations Conflict of interest The authors declare no competing interests. Ethical approval It is not applicable. Consent to participate It is not applicable. Consent for publication It is not applicable., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Radiotherapy combined with a radiosensitizer represents an important treatment for head and neck squamous cell carcinoma (HNSCC). Only a few chemotherapy agents are currently approved as radiosensitizers for targeted therapy. Oral squamous cell carcinoma is one of the deadliest cancers, with approximately ~500,000 new diagnosed cases and 145,000 deaths worldwide per year. The incidence of new cases continues to increase in developing countries. This study aimed to investigate the effect of Croton tonkinensis and Curcuma longa on cell viability in OSCC cells. The HNSCC cell line OML1 and its radiation-resistant clone OML1-R were used. The anticancer effect and the mechanism of action of Croton tonkinensis and Curcuma longa in OSCC cells were analyzed by using cell viability assays, Western blot analysis, and Tranwell migration assays. The results showed that Croton tonkinensis concentration-dependently reduced the viability of OML1 and OML1-R (radioresistant) cells by downregulating the levels of AKT/mTOR mediators, such as p110α, p85, pAKT (ser473), p-mTOR (ser2448), and p-S6 Ribosomal (ser235/236). We found that cotreatment of OML1 and OML1R cells with either zVAD-FMK (apoptosis inhibitor), Ferrostatin-1 (Fer-1, a ferroptosis inhibitor), or chloroquine (CQ, an autophagy inhibitor) markedly reduced cell death. These results demonstrate that Croton tonkinensis exhibits anti-proliferation activity and highlight the therapeutic potential of small-molecule inhibitors against PI3K/mTOR signaling for radiosensitization in HNC treatment.

Background/aim: Natural compounds such as propolis have gained wide popularity in the last decades. While its antibacterial, antiviral, and antifungal properties are well known, the anticancer properties of propolis are just beginning to be appreciated. Herein, we comparatively investigate the cytotoxic and radiosensitizing potential of four different ethanolic propolis extracts originating from three different countries (Germany, Ireland, South Africa) in human lung cancer cell models., Materials and Methods: Liquid chromatography-mass spectrometry (LC-MS/MS) was applied to characterize the four different propolis extracts. Cytotoxicity and radiation survival were determined by 3D matrix-based clonogenic assays and autophagy was examined by western blotting., Results: We found cytotoxicity in a propolis type-, time- and cell model- dependent manner. In the four ethanolic propolis extracts, Coumaric acid, Caffeic acid phenethyl ester, Pinocembrin and Chrysin presented the major compounds identified. Examining the induction of autophagy using the marker LC3B and autophagy inhibition with chloroquine suggested autophagy to be part of the survival mechanisms upon propolis treatment in a cell model-dependent manner. Combining propolis with X-ray irradiation showed the radiosensitizing potential of propolis in human lung cancer cell models, which clearly presented in a manner dependent on the incubation time of propolis and the cell model treated., Conclusion: Propolis treatment showed cytotoxic and radiosensitizing effects of propolis on human lung cancer cells. Since these effects differ greatly between the four propolis extracts studied and originating from different regions, further studies are urgently needed to differentiate propolis species and their anticancer properties in more detail., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Despite the established antitumor effectiveness and synergistic interactions of melatonin with photon irradiation, its role in carbon-ion radiotherapy remains uncertain. This study aimed to elucidate the mechanisms and potential clinical advantages of combining exogenous melatonin therapy with carbon-ion radiotherapy., Materials and Methods: The investigation assessed the impact of combining exogenous melatonin with photon or carbon-ion irradiation on cell-cycle modulation and DNA-repair capability using the melanoma cell line B16F10. RNA sequencing and bioinformatics analysis were conducted to explore mechanisms and evaluate potential clinical benefits, with validation performed on the osteosarcoma cell line LM8., Results: Pre-treatment with melatonin reduced the survival fraction of B16F10 and LM8 cells upon exposure to photon and carbon-ion radiation. Mechanistically, melatonin was found to inhibit G 2 /M arrest, preserve DNA damage, and suppress key genes involved in DNA double-strand break repair after 8 Gy carbon-ion radiation. Furthermore, RNA sequencing and bioinformatics analysis revealed favorable changes in genes associated with survival and metastasis, highlighting potential clinical significance. LM8 cells treated with melatonin exhibited increased radiosensitivity and suppression of DNA-repair proteins., Conclusion: The combination of exogenous melatonin not only heightened radiosensitivity and modulated hallmark tumor gene sets in vitro but also markedly suppressed the efficiency of DNA double-strand break-repair pathway, thus enhancing the cytotoxicity of carbon-ion radiotherapy., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Radiation therapy is utilized for treatment of localized prostate cancer. Nevertheless, cancerous cells frequently develop radiation resistance. While higher radiation doses have not always been effective, radiosensitizers have been extensively studied for their ability to enhance the cytotoxic effects of radiation. So, this study aims to evaluate the possible radiosensitization effects of docetaxel (DTX) and silver nanoparticles (SNP) in LNCaP cells., Methods: The cytotoxic effects of DTX, SNP and 2 Gy of X-Ray radiation treatments were assessed in human LNCaP cell line using the MTT test after 24 h. Moreover, the effects of DTX, SNP and radiation on Epidermal growth factor (EGF), Caspase 3, inducible nitric oxide synthase and E-cadherin gene expression were analyzed using the Real-time PCR method. The level of Hydrogen peroxide (H 2 O 2 ), an oxidative stress marker, was also detected 24 h after various single and combined treatments., Results: The combinations of SNP (in low toxic concentration) and/or DTX (0.25× IC 50 and 0.5 × IC 50 concentrations for triple and double combinations respectively) with radiation induced significant cytotoxicity in LNCaP cells in comparison to monotherapies. These cytotoxic effects were associated with the downregulation of EGF mRNA. Additionally, H 2 O 2 levels increased after Radiation + SNP + DTX triple combination and double combinations including Radiation + SNP and Radiation + DTX versus single treatments. The triple combination treatment also increased Caspase 3 and and E-cadherin mRNA levels in compared to single treatments in LNCaP cells., Conclusion: Our results indicate that the combination of SNP and DTX with radiation induces significant anti-cancer effects. Upregulation of Caspase 3 and E-cadherin gene expression, and decreased mRNA expression level of EGF may be exerted specifically by use of this combination versus single treatments., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

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.

Radiotherapy (RT) is a frequently used means in clinical tumor treatment. The outcome of RT varies, however, to a great extent, due to RT resistance or intolerable dose, which might be resolved by the development of radio-sensitizing strategies. Here, we report redox-sensitive iodinated polymersomes (RIP) carrying histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA, vorinostat), as a new dual-functional nano-radiosensitizer for breast cancer radiotherapy. SAHA-loaded RIP (RIP-SAHA) with a size of about 101 nm exhibited good colloidal stability while the reduction-activated release of SAHA, giving rise to better antitumor effect to 4T1 breast carcinoma cells than free SAHA. Accordingly, RIP-SAHA combined with a 4 Gy dose of X-ray radiation led to significantly enhanced suppression of 4T1 cells compared with SAHA combined 4 Gy of X-ray radiation, as a result of enhanced DNA damage and impeded DNA damage repair. The pharmacokinetics and biodistribution studies by single-photon emission computed tomography (SPECT) with 125 I-labeled SAHA ( 125 I-SAHA) showed a 17.3-fold longer circulation and 237.7-fold better tumor accumulation of RIP-SAHA over SAHA. The systemic administration of RIP-SAHA greatly sensitized radiotherapy of subcutaneous 4T1 breast tumors and brought about significant inhibition of tumor growth, without causing damages to major organs, compared with radiotherapy alone. RIP not only enhanced SAHA delivery but also acted as a radiosensitizer. RIP-SAHA emerges as a smart dual-functional nano-radiosensitizer to effectively enhance tumor radiotherapy.

2-Ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16) is an in silico-designed estradiol analogue which has improved the parent compound's efficacy in anti-cancer studies. In this proof-of-concept study, the potential radiosensitizing effects of ESE-16 were investigated in an in vitro deconstructed bone metastasis model. Prostate (DU 145) and breast (MDA-MB-231) tumor cells, osteoblastic (MC3T3-E1) and osteoclastic (RAW 264.7) bone cells and human umbilical vein endothelial cells (HUVECs) were representative components of such a lesion. Cells were exposed to a low-dose ESE-16 for 24 hours prior to radiation at non-lethal doses to determine early signaling and molecular responses of this combination treatment. Tartrate-resistant acid phosphatase activity and actin ring formation were investigated in osteoclasts, while cell cycle progression, reactive oxygen species generation and angiogenic protein expression were investigated in HUVECs. Increased cytotoxicity was evident in tumor and endothelial cells while bone cells appeared to be spared. Increased mitotic indices were calculated, and evidence of increased deoxyribonucleic acid damage with retarded repair, together with reduced metastatic signaling was observed in tumor cells. RAW 264.7 macrophages retained their ability to differentiate into osteoclasts. Anti-angiogenic effects were observed in HUVECs, and expression of hypoxia-inducible factor 1-α was decreased. Through preferentially inducing tumor cell death and potentially inhibiting neovascularization whilst preserving bone physiology, this low-dose combination regimen warrants further investigation for its promising therapeutic application in bone metastases management, with the additional potential of limited treatment side effects.

While investigating the possible synergistic effect of the conventional anticancer therapies, which, taken individually, are often ineffective against critical tumors, such as central nervous system (CNS) ones, the design of a theranostic nanovector able to carry and deliver chemotherapy drugs and magnetic hyperthermic agents to the target radiosensitizers (oxygen) was pursued. Alongside the original formulation of polymeric biodegradable oxygen-loaded nanostructures, their properties were fine-tuned to optimize their ability to conjugate therapeutic doses of drugs (doxorubicin) or antitumoral natural substances (curcumin). Oxygen-loaded nanostructures (diameter = 251 ± 13 nm, ζ potential = -29 ± 5 mV) were finally decorated with superparamagnetic iron oxide nanoparticles (SPIONs, diameter = 18 ± 3 nm, ζ potential = 14 ± 4 mV), producing stable, effective and non-agglomerating magnetic nanovectors (diameter = 279 ± 17 nm, ζ potential = -18 ± 7 mV), which could potentially target the tumoral tissues under magnetic driving and are monitorable either by US or MRI imaging.

Background: The treatment of pelvic malignancies has continued to improve over recent years, with neoadjuvant radiotherapy often considered the gold standard to downstage disease. Radiosensitisers are routinely employed in an attempt to improve response of cancers to radiotherapy. Previous preclinical evidence has suggested a role for metformin, a commonly used drug for type 2 diabetes., Method: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases using the search criteria string 'Metformin' AND ('Radiosensitivity' OR 'radiosensitising' OR 'radiosensitising'). Additional papers were detected by scanning the references of relevant papers. Data were extracted from each study by two authors onto a dedicated proforma. The review was registered on the PROSPERO database (ID: CRD42020199066)., Results: A total of 242 papers were identified, 11 of which were included in this review; an additional 5 papers were obtained from reference searches. Metformin has been demonstrated to reduce cell-viability post-radiotherapy in both rectal and prostate cancer cell lines, with an enhanced effect in tumours with a p53 mutation and increased apoptosis post-radiotherapy for cervical cancer. Clinical trials demonstrate improved tumour and nodal downstaging and pCR rates for rectal cancer using metformin as a radiosensitiser., Conclusion: With an increasing understanding of the underlying mechanism of the effects on metformin prospective studies are required to assess the effect of routine use on cancer related outcomes. Progressive future studies may be better served by the use of predictive biomarker guided treatment to enable identification of the appropriate cohort to target., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Statins, small molecular 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are widely used to lower cholesterol levels in lipid-metabolism disorders. Recent preclinical and clinical studies have shown that statins exert beneficial effects in the management of breast cancer by increasing recurrence free survival. Unfortunately, the underlying mechanisms remain elusive., Materials and Methods: Simvastatin, one of the most widely prescribed lipophilic statins was utilized to investigate potential radiosensitizing effects and an impact on cell survival and migration in radioresistant breast cancer cell lines., Results: Compared to parental cell counterparts, radioresistant MDA-MB-231-RR, T47D-RR andAu565-RR cells were characterized by upregulation of 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR) expression accompanied by epithelial-to-mesenchymal transition (EMT) activation. Radioresistant breast cancer cells can be killed by simvastatin via mobilizing of a variety of pathways involved in apoptosis and autophagy. In the presence of simvastatin migratory abilities and vimentin expression is diminished while E-cadherin expression is increased., Conclusions: The present study suggests that simvastatin may effectively eradicate radioresistant breast carcinoma cells and diminish their mesenchymal phenotypes., (© 2021 Bertram Aschenbrenner, Giulia Negro, Dragana Savic, Maxim Sorokin, Anton Buzdin, Ute Ganswindt, Maja Cemazar, Gregor Sersa, Sergej Skvortsov, Ira Skvortsova, published by Sciendo.)

Objective: The objective of this study is to explore the radiosensitization effects of duramycin against the liver cancer hepatoma cells and relationship to reactive oxygen species (ROS) generation., Materials and Methods: MCA-RH 7777 cells were treated with various combinations of duramycin concentrations and radiation doses. After the treatment, cell viabilities were determined by a cell proliferation assay; intracellular ROS levels were detected with the flow cytometric method., Results: MCA-RH 7777 cell viability was found significantly reduced after combining duramycin and radiation exposure (comparing to that of either treatment alone). Increased intracellular ROS levels were observed in cells treated with combinations of duramycin and radiation., Conclusion: Duramycin increased the intracellular ROS generation and also increased the radiosensitivity of MCA-RH 7777 cells., Competing Interests: None

Background/aim: Improvement of the efficacy of radiotherapy for lung cancer and glioblastoma is urgently needed., Materials and Methods: We synthesized several novel DNA methyltransferase inhibitors and evaluated their potentials as possible radiosensitizers. Eleven non-nucleoside compounds were synthesized and evaluated along with one known compound using human lung cancer (A549) and glioblastoma (U373MG) cells. Cytotoxicity and radiosensitizing effects were evaluated using clonogenic assay. Sensitizer enhancement ratios at a survival fraction of 0.5 were calculated, and statistical analysis was performed using the ratio paired t-test. The inhibitory effects of three selected compounds on the activity of DNA methyltransferase 1 (DNMT1) and the pharmacokinetic profiles were analyzed., Results: All twelve compounds demonstrated various levels of cytotoxicity. Of the twelve compounds, eleven and eight compounds radiosensitized A549 and U373MG cells, respectively, with at least marginal significance (p<0.10). The sensitizer enhancement ratios in A549 and U373MG ranged 1.166-2.537 and 1.083-1.743 among compounds with radiosensitizing effects, respectively. The three selected compounds inhibited DNMT1 activity by 26.5-78.5%. Elimination half-lives ranged from 0.3 to 1.3 h., Conclusion: Novel DNA methyltransferase inhibitors with significant radiosensitizing capacity and improved biostability were synthesized. These materials will serve as a basis for the development of novel radiosensitizers., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A library of iodoquinazolinones endowed with benzenesulfonamide moiety was designed and synthesized as human carbonic anhydrase (hCA) inhibitors. Compounds 4-17 showed generally poor activity against the cytosolic hCA I and hCA II isoforms. Contrarily they were more potent and showed a variable spectrum of selectivity against the tumor-specific isoforms hCA IX and hCA XII. The 4-iodophenyl derivative 12 and the 4-pyridinyl derivative 15 were the most active and selective in this series against hCA IX and hCA XII isoforms with K I of 18 and 9 nM, respectively. Compounds 12 and 15 were further screened for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines besides WI38 and MCF-10A normal cell lines to determine their selectivity towards cancer cells. Compound 12 was selective towards HepG-2 and HCT-116 cell lines but less selective towards MCF-7. While compound 15 showed higher selectivity towards HepG-2 than HCT-116 and MCF-7 cell lines. The ability of compounds 12 and 15 to sensitize the cells against gamma irradiation's effect proved their potential radiosensitizing activity. Molecular docking analysis was carried out to discover the possible binding mode of the compounds within the active site of isoform hCA IX and XII. Compounds 12 and 15 revealed the probable fundamental interactions explaining the good activity and selectivity towards the tumor-specific isoforms., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Solid tumors inevitably develop radioresistance due to low oxygen partial pressure in the tumor microenvironment. Despite numerous attempts, there are still few effective ways to avoid the hypoxia-induced poor radiotherapeutic effect. To overcome this problem, platinum (Pt) nanodots were fabricated into a mesoporous bismuth (Bi)-based nanomaterial to construct a biodegradable nanocomposite BiPt-folic acid-modified amphiphilic polyethylene glycol (PFA). BiPt-PFA could act as a radiosensitizer to enhance the absorption of X-rays at the tumor site and simultaneously trigger response behaviors related to the tumor microenvironment due to the enrichment of materials in the tumor area. During this process, the Bi-based component consumed glutathione via coordination, thus altering the oxidative stress balance, while Pt nanoparticles catalyzed the decomposition of hydrogen peroxide to generate oxygen, thereby relieving tumor hypoxia. Both Pt and Bi thus co-modulated the tumor microenvironment to improve the radiotherapeutic effect. In addition, Pt dots in BiPt-PFA had strong near-infrared absorption ability and created an intensive photothermal therapeutic effect. Modulation of the tumor microenvironment could thus improve the therapeutic effect in hypoxic tumors by a combination of photothermal therapy and enhanced radiotherapy. BiPt-PFA, as a biodegradable nanocomposite, may thus modulate the tumor microenvironment to enhance the hypoxic tumor therapeutic effect by thermoradiotherapy.

To increase the efficiency of therapy via enhancing its selectivity, the usage of gold nanorods (GNR) as a factor sensitizing cancer cells to radiation was proposed. Due to gold nanoparticles' characteristics, the smaller doses of radiation would be sufficient in the treatment, protecting the healthy tissue around the tumor. The aim of this study was to investigate the effect of gold nanorods on cancer and normal prostate cells and the role of nanorods in the cell response to ionizing radiation. The effect was evaluated by measuring the toxicity, cell cycle, cell granularity, reactive oxygen species (ROS) level, and survival fractions. Nanorods showed a strong toxicity dependent on the concentration and incubation time toward all used cell lines. A slight effect of nanorods on the cycle distribution was observed. The results demonstrated that the administration of nanorods at higher concentrations resulted in an increased level of generated radicals. The results of cellular proliferation after irradiation are ambiguous; however, there are noticeable differences after the application of nanorods before irradiation. The obtained results lead to the conclusion that nanorods affect the physiology of both normal and cancer cells. Nanorods might become a potential tool used to increase the effectiveness of radiation treatment.

Enhancing the effectiveness of colorectal cancer treatment is highly desirable. Radiation-based anticancer therapy-such as proton therapy (PT)-can be used to shrink tumors before subsequent surgical intervention; therefore, improving the effectiveness of this treatment is crucial. The addition of noble metal nanoparticles (NPs), acting as radiosensitizers, increases the PT therapeutic effect. Thus, in this paper, the effect of novel, gold-platinum nanocauliflowers (AuPt NCs) on PT efficiency is determined. For this purpose, crystalline, 66-nm fancy shaped, bimetallic AuPt NCs were synthesized using green chemistry method. Then, physicochemical characterization of the obtained AuPt NCs by transmission electron microscopy (TEM), selected area electron diffraction (SAED), energy dispersive X-ray spectroscopy (EDS), and UV-Vis spectra measurements was carried out. Fully characterized AuPt NCs were placed into a cell culture of colon cancer cell lines (HCT116, SW480, and SW620) and a normal colon cell line (FHC) and subsequently subjected to proton irradiation with a total dose of 15 Gy. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test, performed after 18-h incubation of the irradiated cell culture with AuPt NCs, showed a significant reduction in cancer cell viability compared to normal cells. Thus, the radio-enhancing features of AuPt NCs indicate their potential application for the improvement in effectiveness of anticancer proton therapy.

The purpose of this study was to determine if radiation (RT)-resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radiosensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN -/- cells engineered by CRISPR/Cas9, were used for mechanistic studies performed in vitro in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope-labeled substrates, metabolic rescue, and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and RT. In vivo studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune-compromised mice. PI3K-activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine-dependent PI3K-activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radiosensitized cervical cancer cells in vitro and in vivo These novel preclinical data support the utility of telaglenastat for glutamine-dependent radioresistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity., (©2020 American Association for Cancer Research.)

Trifluridine/tipiracil (FTD/TPI; marketed as Lonsurf®) has shown clinically relevant activity after fluoropyrimidine failure in colorectal cancer and may thus be of increased efficacy compared with current standard capecitabine chemoradiation. Here we investigated the colorectal cancer cell lines HT29, HCT116, SW48 and Caco-2 to provide a preclinical rationale for FTD/TPI-based chemoradiation treatment. All lines incorporated similar amounts of FTD, irrespective of treatment concentration and duration, then arrested in S phase, showed persistent γH2AX induction and eventually underwent endoreplication, resulting in polyploidy. Clonogenic assays performed for four combined treatment schedules demonstrated additivity for treatments given within 6 h of each other. However, 24 h FTD/TPI treatment prior to irradiation caused 1.6-2.4 fold radiosensitisation. Combined in vivo treatment was well tolerated and caused a marked tumour growth delay, similar to capecitabine radiochemotherapy regimes. Prolonged S phase arrest, persistent γH2AX signalling, endoreplication and polyploidy may contribute to the cytotoxicity of FTD/TPI. The strong radiosensitising effect observed in vitro after prolonged treatment with FTD/TPI and equivalence with capecitabine-based chemoradiation in vivo support a daily fractionated combined regime of FTD/TPI and radiation in rectal cancer treatment. This is now being tested in a phase I/II clinical trial (NCT04177602)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Radiotherapy is an essential treatment for endometrial cancer (EC), especially in advanced, metastatic, and recurrent cases. Combining radiotherapy, which mainly causes DNA double-strand breaks (DSBs), with small molecules targeting aberrantly activated homologous recombination (HR) repair pathways holds great potential for treating ECs in advanced stages. Here, we demonstrate that diosmetin (DIO), a natural flavonoid, suppresses HR, therefore inhibiting cell proliferation and enhancing the sensitivity of EC to radiotherapy. Clonogenic experiments revealed that combining DIO and X-ray significantly inhibited the viability of EC cells compared to cells treated with diosmetin or X-ray alone. The survival fraction of EC cells decreased to 40% when combining 0.4 Gy X-ray and 4 μM DIO; however, each treatment alone only caused death in approximately 15% and 22% of cancer cells, respectively. Further mechanistic studies showed that diosmetin inhibited the recruitment of RPA2 and RAD51, two critical factors involved in the HR repair pathway, upon the occurrence of DSBs. Thus, we propose that a combination of diosmetin and irradiation is a promising therapeutic strategy for treating endometrial cancer.

Aim: To explore the radiosensitizing effect of AZD8931, a novel equipotent and reversible inhibitor of signaling by EGFR (HER1), HER2 and HER3 receptors, focusing on cell cycle progression, apoptosis and clonogenic capacity in the human LoVo colorectal cancer (CRC) cell line, also in comparison with the EGFR-blocking monoclonal antibody Cetuximab or the EGFR tyrosine kinase selective small molecular inhibitor Gefitinib., Materials and Methods: Cells were pretreated with EGFR inhibitors for 5 consecutive days and then exposed or not to ionizing radiation (IR) (2 Gy daily for 3 consecutive days). Cell proliferation, cell cycle progression and apoptosis were evaluated by flow cytometry and enzyme-linked immunosorbent assay (ELISA), clonogenic potential and radiosensitivity were studied by colony formation assay., Results: AZD8931 induced cell cycle arrest and apoptosis more effectively than Gefitinib and Cetuximab and, more importantly, it was significantly more potent than Gefitinib and Cetuximab in radiosensitizing cells. This radiosensitizing action by AZD8931 mainly occurred by markedly reducing cell cycle progression into S phase, the most radioresistant phase of cell cycle, secondly by inducing apoptosis and reducing clonogenic survival., Conclusions: Our results show that AZD8931 increases IR efficacy in LoVo cells, suggesting that it works as a potent radiosensitizer, even more efficient than Gefitinib and Cetuximab, opening new pathways of investigation for further in vitro and in vivo studies aimed at confirming its potential to improve local radiotherapy in CRC.

Structure of the fucoidan from Sargassum horneri and products of its enzymatic transformation with molecular weight over 20 kDa were investigated. Fucoidan was hydrolyzed by recombinant fucoidanase FFA1 and its fraction of higher molecular weight was fractionated using anion-exchange chromatography, resulting in three sulphated polysaccharides of various molecular weight (63-138 kDa). Their structures were analyzed using NMR spectroscopy, showing the fucoidan (ShF) to be a branched polysaccharide with the backbone consisting of the repeating →3-α-l-Fucp(2SO 3 - )-1→4-α-l-Fucp(2,3SO 3 - )-1→ fragment and side chains including the α-l-Fucp-1→2-α-l-Fucp-1→ or α-l-Fucp-1→3-α-l-Fucp(4SO 3 - )-1→ fragments attached to the main chain at C4. The fragment F3 differing by molecular weight and side chain from other fucoidans fragments possessed the most significant anticancer and radiosensitizing activities., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Radiation therapy aims to kill or inhibit proliferation of cancer cells while sparing normal cells. To enhance radiosensitization, we developed 40 nm-sized gold nanoparticles targeting the nucleus. We exploited a strategy that combined RGD and NLS peptides respectively targeting cancer cell and the nucleus to initiate cell-death activated by x-ray irradiation. We observed that the modified gold nanoparticles were either translocated in the nuclei or accumulated in the vicinity of the nuclei. We demonstrated that x-ray irradiation at 225 kVp energy reduced cell proliferation by 3.8-fold when the nuclear targeted gold nanoparticles were used. We determined that the radiation dose to have a 10% survival fraction was reduced from 11.0 Gy to 7.1 Gy when 10.0 µg ml -1 of the NLS/RGD/PEG-AuNP was incubated with A549 cancer cells. We conclude that the peptide-modified gold nanoparticles targeting the nucleus significantly enhance radiosensitization.

Background/aim: The cell-killing and radiosensitizing effects of carbon-ion (C-ion) beams with low linear energy transfer (LET) are underexplored. We aimed to demonstrate the cell-killing effects of 60 Co gamma rays and C-ion beams at various LET values and the radiosensitizing effect of C-ion beams at various LET and cisplatin levels., Materials and Methods: Human uterine cervical cancer cells were irradiated with 60 Co gamma rays and C-ion beams at different levels of LET, with and without cisplatin treatment., Results: Low-LET C-ion beams had a superior cell-killing effect compared to 60 Co gamma rays. Survival curves under low-LET C-ion beams were more similar to that of 60 Co gamma rays than that of high-LET C-ion beams. Cisplatin significantly reduced cell survival after 1, 2, and 3 Gy C-ion beam irradiations at LET values of 13/30/70 keV/μm, 13/30 keV/μm, and 13 keV/μm, respectively., Conclusion: Low-LET C-ion beams combined with cisplatin have higher radiosensitizing effects than high-LET C-ion beams., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Newly synthesized platinum(IV) complexes with ethylenediamine-N,N'-diacetate ligands (EDDA-type) (butyl-Pt and pentyl-Pt) were investigated against two cancer (A549 lung, and HTB 140 melanoma) and one non-cancerous (MRC-5 embryonic lung fibroblast) human cell lines., Materials and Methods: The effects of these agents were compared with those of cisplatin after 6-, 24- and 48-h treatment. Sulforhodamine-B (SRB) assay was performed to estimate the cytotoxic effect, while the inhibitory effect on cell proliferation was measured using 5-bromo-2,-deoxyuridine (BrdU) incorporation assay. Cell cycle analysis was performed by flow cytometry. Type of cell death induced by these agents was determined by electrophoretic analysis of DNA, flow cytometry and by western blot analysis of proteins involved in induction of apoptosis. The effects of gamma irradiation, alone and in combination with platinum-based compounds, were examined by clonogenic and SRB assays., Results: All examined platinum-based compounds had inhibitory and antiproliferative effects on A549 cells, but not on HTB140 and MRC-5 cells. Butyl-Pt, pentyl-Pt and cisplatin arrested the cell cycle in the S-phase and induced apoptotic cell death via regulation of expression of B-cell lymphoma 2 (BCL2) and BCL2-associated X (BAX) proteins. Platinum-based compounds increased the sensitivity of A549 cells to gamma irradiation. Butyl-Pt and pentyl-Pt showed better antitumour effects against A549 cells than did cisplatin, by interfering in cell proliferation and the cell cycle, and by triggering apoptosis., Conclusion: The effects of gamma irradiation on tumour cells may be amplified by pre-treatment of cells with platinum-based compounds., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show in vitro that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models in vivo Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both in vitro and in vivo Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium., (©2020 American Association for Cancer Research.)

Magnesium-doped copper spinel ferrite superparamagnetic nanoparticles (Mg (1-x) Cu x Fe 2 O 4 SPMNPs, 0.2 ≤ x ≤ 0.8) were successfully synthesized by a hydrothermal method. The cytotoxicity effects and cell viability of MCF-7 on human breast cancer cells pre and post exposure to the Mg 1-x Cu x Fe 2 O 4 SPMNPs at different concentrations of 0.1, 1, 10 and 100 μg ml -1 under radiotherapy were studied by MTT (3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay. Here, x-ray diffraction, scanning electron microscopy, atomic force microscopy, UV-visible spectrophotometry, Fourier transform infrared spectroscopy and vibrating-sample magnetometry were evaluated for the crystal structure, morphology, optical and magnetic property of the Mg (1-x) Cu x Fe 2 O 4 SPMNPs. The results showed that the Mg (1-x) Cu x Fe 2 O 4 SPMNPs all at x values had no significant cytotoxicity at concentrations of 0.1,1 and 10 μg ml -1 , but were enhanced by increasing of Cu content. Furthermore, cell destruction of MCF-7 human breast cancer cells post exposure to Mg (1-x) Cu x Fe 2 O 4 SPMNPs under x-ray irradiation was enhanced by increasing the Cu content and concentration. Superparamagnetic properties of the Mg (1-x) Cu x Fe 2 O 4 SPMNPs cause their localization and elimination, by only an external magnetic field. In conclusion, the Mg (1-x) Cu x Fe 2 O 4 SPMNPs with optimum values of x = 0.2 (10 μg ml -1 ) and x = 0.6 (1 μg ml -1 ) can be considered as a nano-radiosensitizer because of the synergistic treatment effect without cytotoxicity on the MCF-7 cells.

One of the major issues in cancer radiotherapy (RT) is normal tissue toxicity. Introduction of radiosensitizers like gold nanoparticles (GNPs) into cancer cells to enhance the local RT dose has been tested successfully. However, it is not known how GNPs interact with other stromal cells such as normal fibroblasts (FBs) and cancer associated fibroblasts (CAFs) within the tumour microenvironment. It is known that FBs turn into CAFs to promote tumour growth. Hence, we used FBs and CAFs along with HeLa (our cancer cell line) to evaluate the differences in GNP uptake and resulting radiation induced damage to elucidate the GNP-mediated therapeutic effect in RT. The CAFs had the largest uptake of the GNPs per cell, with on average 265% relative to HeLa while FBs had only 7.55% the uptake of HeLa and 2.87% the uptake of CAFs. This translated to increases in 53BP1-related DNA damage foci in CAFs (13.5%) and HeLa (9.8%) compared to FBs (8.8%) with RT treatment. This difference in DNA damage due to selective targeting of cancer associated cells over normal cells may allow GNPs to be an effective tool in future cancer RT to battle normal tissue toxicity while improving local RT dose to the tumour.

Purpose: Esophageal cancer is a deadly malignancy with a 5-year survival rate of only 5% to 20%, which has remained unchanged for decades. Esophageal cancer possesses a high frequency of TP53 mutations leading to dysfunctional G 1 cell-cycle checkpoint, which likely makes esophageal cancer cells highly reliant upon G 2 -M checkpoint for adaptation to DNA replication stress and DNA damage after radiation. We aim to explore whether targeting Wee1 kinase to abolish G 2 -M checkpoint sensitizes esophageal cancer cells to radiotherapy., Experimental Design: Cell viability was assessed by cytotoxicity and colony-forming assays, cell-cycle distribution was analyzed by flow cytometry, and mitotic catastrophe was assessed by immunofluorescence staining. Human esophageal cancer xenografts were generated to explore the radiosensitizing effect of AZD1775 in vivo ., Results: The IC 50 concentrations of AZD1775 on esophageal cancer cell lines were between 300 and 600 nmol/L. AZD1775 (100 nmol/L) as monotherapy did not alter the viability of esophageal cancer cells, but significantly radiosensitized esophageal cancer cells. AZD1775 significantly abrogated radiation-induced G 2 -M phase arrest and attenuation of p-CDK1-Y15. Moreover, AZD1775 increased radiation-induced mitotic catastrophe, which was accompanied by increased γH2AX levels, and subsequently reduced survival after radiation. Importantly, AZD1775 in combination with radiotherapy resulted in marked tumor regression of esophageal cancer tumor xenografts., Conclusions: Abrogation of G 2 -M checkpoint by targeting Wee1 kinase with AZD1775 sensitizes esophageal cancer cells to radiotherapy in vitro and in mouse xenografts. Our findings suggest that inhibition of Wee1 by AZD1775 is an effective strategy for radiosensitization in esophageal cancer and warrants clinical testing., (©2020 American Association for Cancer Research.)

Tumor hypoxia, acidosis, and excessive reactive oxygen species (ROS) were the main characteristics of the bladder tumor microenvironment (TME), and abnormal TME led to autophagy activation, which facilitated cancer cell proliferation. The therapeutic efficacy of autophagy inhibitors might also be impeded by abnormal TME. To address these issues, we proposed a new strategy that utilized manganese dioxide (MnO 2 ) nanoparticles to optimize the abnormal TME and revitalize autophagy inhibitors, and both oxygenation and autophagy inhibition may sensitize the tumor cells to radiation therapy. Methods: By taking advantage of the strong affinity between negatively charged MnO 2 and positively charged chloroquine (CQ), the nanoparticles were fabricated by integrating MnO 2 and CQ in human serum albumin (HSA)-based nanoplatform (HSA-MnO 2 -CQ NPs). Results: HSA-MnO 2 -CQ NPs NPs efficiently generated O 2 and increased pH in vitro after reaction with H + /H 2 O 2 and then released the encapsulated CQ in a H + /H 2 O 2 concentration-dependent manner. The NPs restored the autophagy-inhibiting activity of chloroquine in acidic conditions by increasing its intracellular uptake, and markedly blocked hypoxia-induced autophagic flux. In vivo studies showed the NPs improved pharmacokinetic behavior of chloroquine and effectively accumulated in tumor tissues. The NPs exhibited significantly decreased tumor hypoxia areas and increased tumor pH, and had remarkable autophagy inhibition efficacy on bladder tumors. Finally, a significant anti-tumor effect achieved by the enhanced autophagy inhibition and radiation sensitization. Conclusions: HSA-MnO 2 -CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Glioblastoma, the most common and aggressive brain tumor with low survival rate, is difficult to be cured by neurosurgery or radiotherapy. Mounting evidence has reported the anti-inflammatory and anticancer effects of curcumin on several types of cancer in preclinical studies and clinical trials. To our knowledge, there is no platform or system that could be used to effectively and real-timely evaluate the therapeutic efficacy of curcumin for glioblastoma multiforme (GBM). In this study, we constructed a lentivirus vector with triple-reporter genes ( Fluc / GFP / tk ) and transduced into rat F98 glioblastoma cells to establish an orthotopic F98/ FGT glioma-bearing rat model. In the model, the therapeutic efficacies for curcumin alone, radiation alone, and their combination were evaluated via noninvasive bioluminescent imaging and overall survival measurements. At the cell level, curcumin is capable of causing a G2/M cell cycle arrest and sensitizing the F98 cells to radiation. In animal model, curcumin synergistically enhances the effects of radiotherapy on suppressing the growth of both transplanted glioma cells and in situ brain tumors, and extending the overall survival periods longer than those of curcumin alone and radiation alone treatments. In conclusion, we have demonstrated that curcumin may serve as a novel radiosensitizer to combine with radiotherapy using the triple-reporter F98/ FGT animal model for effective and simultaneous evaluation of therapeutic efficacy.

The application of nanoparticles (NPs) as radio-sensitizers and carriers has opened up a new horizon to overcome the limitations of chemo and radiotherapy. In this study, bovine serum albumin-coated Bi 2 S 3 NPs (Bi 2 S 3 @BSA NPs) were synthesized and evaluated in terms of their ability to be used as a radio-sensitizer and carrier for methotrexate (MTX). Physicochemical properties of MTX conjugated Bi 2 S 3 @BSA NPs (Bi 2 S 3 @BSA-MTX NPs) were characterized by DLS, TEM, FTIR, UV/Vis, and XRD analyses. After the evaluation of cellular uptake and intracellular localization, the cytotoxicity of the combination of Bi 2 S 3 @BSA-MTX NPs and X-Ray radiation was analyzed against the SW480 cell line. The synthesized NPs exhibited spherical-like shapes and homogenous morphology, possessing a hydrodynamic diameter of 140.2 ± 5.71 nm (mean ± SD) and zeta potential of -25 mV. Also, the release study showed that the release of MTX is faster and higher in the presence of the proteinase K enzyme than the absence of the enzyme. The results of in-vitro chemo-radiation therapy indicated that the viability of treated cells with Bi 2 S 3 @BSA-MTX NPs is significantly lower than the cells treated with Bi 2 S 3 @BSA NPs. Furthermore, cells treated with Bi 2 S 3 @BSA-MTX NPs showed a lower degree of viability when combined with X-Ray radiation in comparison with the absence of irradiation, which confirmed the ability of the Bi 2 S 3 @BSA-MTX NPs as radio-sensitizer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Light-mediated therapy has many unique merits but monotherapy strategies rarely completely inhibit tumor growth because resistance often develops. Combination therapy is a promising strategy in oncology and has demonstrated superior safety and efficacy over monotherapy. Here, we conjugated a scintillator complex and gold nanorod nanosensitizer for dual-modal image-guided photothermal and X-ray-induced photodynamic therapy (PDT). Lanthanide complexes were successfully conjugated and offer excellent X-ray-excited optical luminescence for PDT effects. The strong near-infrared (NIR) light and X-ray absorption abilities of gold nanorods make the nanosensitizer function as both a photothermal agent for photothermal therapy and a radiosensitizer for enhanced radiotherapy. The studies in vitro and in vivo demonstrated that the nanosensitizer offers good dual-modal imaging capability and significantly suppresses tumor progression under NIR light and X-ray irradiation. This work shows the great potential of conjugating scintillator lanthanide complexes and gold nanosensitizers for multimodal image-guided therapy of deep-seated tumors.

Purpose: The incidence of mesothelioma continues to rise and prognosis remains dismal owing to resistance to conventional therapies and few novel treatment options. Failure to activate apoptotic cell death is a resistance mechanism that may be overcome by inhibition of antiapoptotic Bcl-2 proteins using BH3-mimetic drugs. We investigated the role of antiapoptotic proteins in the radioresistance of mesothelioma, identifying clinically relevant targets for radiosensitization and evaluating the activity of BH3-mimetics alone and in combination with radiation therapy in preclinical models., Methods, Materials and Results: Mesothelioma cell lines 211H, H2052, and H226 exposed to BH3-mimetics demonstrated Bcl-xL dependence that correlated with protein expression and was confirmed by genetic knockdown. The Bcl-xL inhibitor A1331852 exhibited cytotoxic (EC 50 , 0.13-1.42 μmol/L) and radiosensitizing activities (sensitizer enhancement ratios, 1.3-1.8). Cytotoxicity was associated with induction of mitochondrial outer membrane permeabilization and caspase-3/7 activation. Efficacy was maintained in a 3-dimensional model in which combination therapy completely eradicated mesothelioma spheroids. Clinical applicability was confirmed by immunohistochemical analysis of Bcl-2 proteins in patient samples and radiosensitizing activity of A1331852 in primary patient-derived mesothelioma cells., Conclusions: Mesothelioma cells exhibit addiction to the antiapoptotic protein Bcl-xL, and their intrinsic radioresistance can be overcome by small molecule inhibition of this novel therapeutic target., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: One of the major issues in current radiotherapy (RT) is the normal tissue toxicity. A smart combination of agents within the tumor would allow lowering the RT dose required while minimizing the damage to healthy tissue surrounding the tumor. We chose gold nanoparticles (GNPs) and docetaxel (DTX) as our choice of two radiosensitizing agents. They have a different mechanism of action which could lead to a synergistic effect. Our first goal was to assess the variation in GNP uptake, distribution, and retention in the presence of DTX. Our second goal was to assess the therapeutic results of the triple combination, RT/GNPs/DTX., Methods: We used HeLa and MDA-MB-231 cells for our study. Cells were incubated with GNPs (0.2 nM) in the absence and presence of DTX (50 nM) for 24 h to determine uptake, distribution, and retention of NPs. For RT experiments, treated cells were given a 2 Gy dose of 6 MV photons using a linear accelerator., Results: Concurrent treatment of DTX and GNPs resulted in over 85% retention of GNPs in tumor cells. DTX treatment also forced GNPs to be closer to the most important target, the nucleus, resulting in a decrease in cell survival and increase in DNA damage with the triple combination of RT/ GNPs/DTX vs RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations., Conclusion: The ability to not only trap GNPs at clinically feasible doses but also to retain them within the cells could lead to meaningful fractionated treatments in future combined cancer therapy. Furthermore, the suggested triple combination of RT/GNPs/DTX may allow lowering the RT dose to spare surrounding healthy tissue., Advances in Knowledge: This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization.

Hypoxia is known to be a common feature within many types of solid tumors, which is closely related to the limited efficacy of radiotherapy. Meanwhile, due to the non-discriminatory killing effect of both normal and cancer cells during the radiation process, traditional radiosensitizers could bring severe non-negligible side-effects to the whole body. In this work, stable and atomically precise Mn clusters which possess efficient pH-triggered catalytic selective capacity are developed rationally. Mn clusters could efficiently catalyze oxygen production in an acidic tumor microenvironment, while exhibiting strong reducibility and free radical scavenging ability in neutral circumstances. In vivo experiments show that Mn clusters are able to enhance the radiotherapy effect in the mouse model of 4T1 tumors and protect normal tissues from radiation at the same time. Thus, the present work provides a novel dual-functional strategy to enhance radiotherapy-induced tumor treatment by improving tumor oxygenation and protect normal tissues from radiation simultaneously.

Every year, more than 500,000 new cases of cervical cancer are reported, making it the fourth leading cause of cancer globally. Although human papillomavirus (HPV) vaccines show promise as a protective measure, HPV-related cancers remain a public health problem since the vaccines, which are only specific to certain viral types, are unavailable for mass distribution. Furthermore, the effects of toxicity following ionizing radiation therapy have reoriented views toward the search for radiosensitizers that can reduce toxicity as a consequence of decreased radiation doses. Here, we isolated ergosterol peroxide (EP) from Pleurotus ostreatus and purified it to test its potential effects in vitro. We thus observed that a gradual increase in EP dose correlates with a loss of viability in HeLa and CaSki cervical cell lines. Dose/response curves were constructed using cervical cancer cell lines, as well as normal human peripheral blood mononuclear cells. The selectivity of EP in human lymphocytes and cervical cancer cell lines was tested, and no toxicity was found in normal cells. A combination of treatments revealed a radiosensitizer effect in HeLa cells, when measuring the exposure to EP followed by irradiation with 137Cs. Our findings suggest that EP may be effective as a radiosensitizer in treating cervical cancer.

Purpose To elucidate the radiosensitizing effect and underlying mechanism of a new kind of DNA methyltransferase (DNMT) inhibitor with biological availability. Methods A novel non-nucleoside compound, designated as MA-17, was recently derived from a phthalimido alkanamide structure. DNMT expressions were confirmed in cultured human lung cancer (A549) and normal astrocyte (NHA) cells, radiosensitivity was measured using clonogenic assay, and assays of cell cycle alteration, apoptosis, DNA damage repair, and differential gene expression were undertaken. Results MA-17 significantly radiosensitized A549 cells with a mean dose enhancement ratio (DER) of 1.43 at the surviving fraction of 0.2 (p < 0.05 by one-tailed ratio paired t-test). MA-17 did not affect normal astrocytes (mean DER 0.2 , 1.016; p = 0.420). MA-17 demonstrated a mean half-life of 1.0 h in vivo and a relatively even distribution in various tissues. Pretreatment with MA-17 increased sub-G1 fractions and inhibited the repair of DNA double-strand breaks, which are induced by irradiation. We found that MA-17 also down-regulated DNA homologous recombination and the Fanconi anemia pathway (FANCA, BRCA1, and RAD51C) in A549 cells. This bioinformatics finding was confirmed in validation Western blot to evaluate the expression of vital proteins. Conclusions A novel phthalimido alkanamide derivative, a DNMT inhibitor, possessed both biostability and favorable and substantial radiosensitizing effects by augmenting apoptosis or inhibiting DNA damage repair.

Background: Metal nanomaterials have a significant potential as photosensitizer and radiosensitizer. The purpose of this study was to evaluate the cytotoxicity of a platinum mesoporous nanostructure (Pt MN) toward a melanoma cancer cell line upon combined laser radiation (808 nm, 1 and 1.5 W cm -2 ) and X-ray irradiation (6 MV, 2, 4, and 6 Gy)., Methods: Pt MN was synthesized by a simple procedure and characterized by field emission scanning and transmission electron microscopy. A mouse malignant melanoma cell line C540 (B16/F10) was treated with Pt MN, laser light and/or X-ray., Results: Pt MN had a mesoporous structure with a sponge-resemble shape comprised of ensembles of very small adhered particles of <11 nm and about 5-nm pores. While Pt MN represented a low toxicity toward and considerable uptake into the cell line in a concentration range of 10-100 μg mL -1 , laser light radiation alone was also not toxic, and X-ray irradiation alone induced a limited toxicity, Pt MN was toxic against the cells in a dose dependent manner upon laser light radiation, X-ray irradiation, or their combined exposure. The killing efficacy of Pt MN upon X-ray irradiation was more obvious at 72 h post-treatment. The combined exposure (laser radiation followed by X-ray irradiation) led to a deep cell killing and a very low melanoma cell viability (∼1%). Significant melanoma cancer cell killing of Pt MN was due to reactive oxygen species (ROS) production upon combined exposure of laser and X-ray, while cell killing upon laser light radiation was due to heat generation., Conclusion: Pt MN was introduced as a supreme laser/X-ray sensitizer for treatment of cancer with a high ability to produce ROS and a potent impact on decreasing cell viability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Boron neutron capture therapy (BNCT) selectively kills tumor cells while sparing adjacent normal cells. Boric acid (BA)-mediated BNCT showed therapeutic efficacy in treating hepatocellular carcinoma (HCC) in vivo. However, DNA damage and corresponding responses induced by BA-mediated BNCT remained unclear. This study aimed to investigate whether BA-mediated BNCT induced DNA double-strand breaks (DSBs) and to explore DNA damage responses in vitro., Materials and Methods: Huh7 Human HCC cells were treated with BA and irradiated with neutrons during BA-BNCT. Cell survival and DNA DSBs were examined by clonogenic assay and expression of phosphorylated H2A histone family member X (γH2AX), respectively. The DNA damage response was explored by determining the expression levels of DNA repair- and apoptosis-associated proteins and conducting a cell-cycle analysis., Results: DNA DSBs induced by BA-mediated BNCT were primarily repaired through the homologous recombination pathway. BA-mediated BNCT induced G 2 /M arrest and apoptosis in HCC., Conclusion: Our findings may enable the identification of radiosensitizers or adjuvant drugs for potentiating the therapeutic effectiveness of BA-mediated BNCT for HCC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Cervical cancer is one of the most common causes of cancer-associated mortality among affected women in the world. At present, treatment with weekly cisplatin plus ionizing radiation (IR) therapy is the standard regimen for cervical cancer, especially for locally advanced cervical cancer. The purpose of this study is to determine whether FEN1 inhibitors could enhance the therapeutic effect of IR therapy., Methods: Western blot was applied to determine the expression of FEN1- and apoptosis-related proteins. Cell growth inhibition assay and colony formation assay were used to determine the effects of FEN1 inhibitor and IR exposure for Hela cells in vitro. CRISPR technology was used to knockdown FEN1 expression level of 293T cells, and tumor xenograft in nude mice was employed to determine the effects of FEN1 inhibitor and IR exposure on tumor growth in vivo., Results: Our data revealed that FEN1 is overexpressed in HeLa cell and can be upregulated further by IR. We also demonstrated that FEN1 inhibitor enhances IR sensitivity of cervical cancer in vitro and in vivo., Conclusion: FEN1 inhibitor SC13 could sensitize radiotherapy of cervical cancer cell., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Mechanistic approaches to modeling the effects of ionizing radiation on cells are on the rise, promising a better understanding of predictions and higher flexibility concerning conditions to be accounted for. In this work we modified and extended a previously published mechanistic model of cell survival after photon irradiation under hypoxia to account for radiosensitization caused by deficiency or inhibition of DNA damage repair enzymes. The model is shown to be capable of describing the survival data of cells with DNA damage repair deficiency, both under norm- and hypoxia. We find that our parameterization of radiosensitization is invariant under change of oxygen status, indicating that the relevant parameters for both mechanisms can be obtained independently and introduced freely to the model to predict their combined effect., Competing Interests: Amir Abdollahi and Jürgen Debus received research funds from Merck KGaA, Darmstadt, Germany, and are involved as academic mentors in the DNA-Repair Cluster initiative with Merck KGaA-BioMedX. Frank T. Zenke is an employee of Merck KGaA, Darmstadt, Germany. The other authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Background: Limited effective intervention for advanced hepatocellular carcinoma (HCC) is available. This study aimed to investigate the potential clinical utility of apatinib, a highly selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, as a radiosensitizer in the treatment of HCC., Methods: Four human HCC cell lines SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B were treated with apatinib, irradiation or combination treatment. Colony formation assay, flow cytometry and nuclear γ-H2AX foci immunofluorescence staining were performed to evaluate the efficacy of combination treatment. RNA sequencing was conducted to explore the potential mechanism. The impact of combination treatment on tumor growth was assessed by xenograft mice models., Results: Colony formation assay revealed that apatinib enhanced the radiosensitivity of HCC cell lines. Apatinib suppressed repair of radiation-induced DNA double-strand breaks. Flow cytometry analysis showed that apatinib increased radiation-induced apoptosis. Apatinib radiosensitized HCC via suppression of radiation-induced PI3K/AKT pathway. Moreover, an in vivo study indicated apatinib combined with irradiation significantly decreased xenograft tumor growth., Conclusions: Our results indicate that apatinib has therapeutic potential as a radiosensitizer in HCC, and PI3K/AKT signaling pathway plays a critical role in mediating radiosensitization of apatinib.

Sustained locoregional control of disease is a significant issue in patients with inflammatory breast cancer (IBC), with local control rates of 80% or less at 5 years. Given the unsatisfactory outcomes for these patients, there is a clear need for intensification of local therapy, including radiation. Inhibition of the DNA repair protein PARP1 has had little efficacy as a single agent in breast cancer outside of studies restricted to patients with BRCA mutations; however, PARP1 inhibition (PARPi) may lead to the radiosensitization of aggressive tumor types. Thus, this study investigates inhibition of PARP1 as a novel and promising radiosensitization strategy in IBC. In multiple existing IBC models (SUM-149, SUM-190, MDA-IBC-3), PARPi (AZD2281-olaparib and ABT-888-veliparib) had limited single-agent efficacy (IC 50 > 10 μmol/L) in proliferation assays. Despite limited single-agent efficacy, submicromolar concentrations of AZD2281 in combination with RT led to significant radiosensitization (rER 1.12-1.76). This effect was partially dependent on BRCA1 mutational status. Radiosensitization was due, at least in part, to delayed resolution of double strand DNA breaks as measured by multiple assays. Using a SUM-190 xenograft model in vivo , the combination of PARPi and RT significantly delays tumor doubling and tripling times compared with PARPi or RT alone with limited toxicity. This study demonstrates that PARPi improves the effectiveness of radiotherapy in IBC models and provides the preclinical rationale for the opening phase II randomized trial of RT ± PARPi in women with IBC (SWOG 1706, NCT03598257)., (©2019 American Association for Cancer Research.)

The current study aimed to identify the radiosensitizing effect of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in combination with radiotherapy in non-small-cell lung cancer (NSCLC) cells. The combination of celecoxib potentiated radiation-induced apoptosis; however, no changes in cell cycle distribution and number of phosphorylated histone H2AX foci were detected, indicating a DNA damage-independent mechanism. In an in vivo mouse model, the tumor size was significantly decreased in the group combining celecoxib with radiation compared with the radiation only group. Phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), as well as expression of COX-2 were significantly downregulated in cells treated with the combination of celecoxib and radiation compared with the radiation only group. The result indicated that celecoxib exhibits radiosensitizing effects through COX-2 and Akt/mTOR-dependent mechanisms. Induction the Akt/mTOR signaling pathway promotes radioresistance in various cancers, including NSCLC. Therefore, the current study suggested the therapeutic potential of combination therapy of celecoxib and radiation in the prevention of radioresistance., Competing Interests: The authors have declared that no competing interests exist.

Aims: Conventional radiotherapy is mainly restricted by the low radiation absorption efficiency of tumors tissues and the hypoxic tumor cells radio-resistance. In this paper, novel nano-radiosensitizers, magnetic nanoparticles core coated with silica, were successfully prepared to overcome these limitations., Main Methods: The prepared nanoparticles have been characterized by transmission electron microscope (TEM), Dynamic light scattering (DLS), atomic force microscope (AFM) and vibration sample magnetometer (VSM). MTT cytotoxicity and DNA double-strand breaks (Comet) assays have been used to assess the radio-enhancing effect of iron oxide magnetic nanoparticles (IO-MNPs) and silica-coated iron oxide magnetic nanoparticles (SIO-MNPs) against MCF7 breast cancer cells. MCF7 cells were treated with different concentrations of the prepared nanoformulations and exposed to an electron beam at doses 0, 0.5, 1, 2, 4 Gy., Key Findings: DLS measurements revealed that the main hydrodynamic diameter of the prepared IO-MNPs and SIO-MNPs was 18.17 ± 4.5 nm and 164.18 ± 16.1 nm, respectively, which was confirmed by TEM micrographs. MTT and comet assays results showed that the radiosensitizing effect of the prepared nanoformulations was dose and concentration dependent. Interestingly, the dose enhancement factor (DEF) for SIO-MNPs was, on average, 1.3-fold greater than that of IO-MNPs., Significance: Coating of IO-MNPs with silica led to enhance their electron radiosensitization and consequently their therapeutic efficacy. Therefore, SIO-MNPs represent a promising engineered nano-formulation for enhancing breast cancer radiosensitivity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Radiotherapy is one of the most common treatments for cancer, but radioresistance and injury to normal tissue are considered major obstacles to successful radiotherapy. Thus, there is an urgent need to develop radiosensitizers to improve the therapeutic outcomes of radiotherapy in cancer patients. Our previous efforts to identify novel radiosensitizers, using high-throughput screening targeting p53 and Nrf2 revealed a promising N -phenylpyrimidin-2-amine (PPA) lead compound. In the present study, 17 derivatives of this lead compound were examined, and it was found that 4-(4-fluorophenyl)-N-(4-nitrophenyl)-6-phenylpyrimidin-2-amine (PPA5), 4-((4-(4-fluorophenyl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl -benzamide (PPA13), 4-((4-(4-fluorophenyl)pyrimidin-2-yl)amino)benzenesulfonamide (PPA14), 4-((4-(2-chlorophenyl)pyrimidin-2-yl)amino)benzenesulfonamide (PPA15), and 4-((4-(2-chlorophenyl)pyrimidin-2-yl)amino)-N-methylbenzamide (PPA17) inhibited cell viability by more than 50%, with a marked increase in the proportion of cells arrested at the G 2 /M phase of cell cycle. Among these compounds, PPA15 markedly increased the sub-G 1 cell population and increased the levels of cyclin B1 and the phosphorylation levels of cyclin-dependent kinase (CDK) 1. Combined treatment with radiation and PPA14 or PPA15 significantly decreased clonogenic survival. An in vitro kinase assay revealed that PPA15 inhibited multiple CDKs involved in cell cycle regulation. Compared with drug or radiation treatment alone, combined treatment with PPA15 and radiation resulted in the suppression of A549 tumor growth in mice by 59.5% and 52.7%, respectively. Treatment with PPA15 alone directly inhibited tumor growth by 25.7%. These findings suggest that the novel pan CDK inhibitor, PPA15, may be a promising treatment to improve the effectiveness of radiotherapy for the treatment of cancer. SIGNIFICANCE STATEMENT: Several inhibitors of CDK have been successfully evaluated in combination with other chemotherapeutics in clinical trials, but negative side effects have partially restricted their clinical use. In this study, we identified a novel pan-CDK inhibitor to increase radiosensitivity, and we hope this work will encourage the development of promising small-molecule radiosensitizers., (Copyright © 2019 by The Author(s).)

Radiosensitizing properties of substituted uridines are of great importance for radiotherapy. Very recently, we confirmed 5-iodo-4-thio-2'-deoxyuridine (ISdU) as an efficient agent, increasing the extent of tumor cell killing with ionizing radiation. To our surprise, a similar derivative of 4-thio-2'-deoxyuridine, 5-bromo-4-thio-2'-deoxyuridine (BrSdU), does not show radiosensitizing properties at all. In order to explain this remarkable difference, we carried out a radiolytic (stationary and pulse) and quantum chemical studies, which allowed the pathways to all radioproducts to be rationalized. In contrast to ISdU solutions, where radiolysis leads to 4-thio-2'-deoxyuridine and its dimer, no dissociative electron attachment (DEA) products were observed for BrSdU. This observation seems to explain the lack of radiosensitizing properties of BrSdU since the efficient formation of the uridine-5-yl radical, induced by electron attachment to the modified nucleoside, is suggested to be an indispensable attribute of radiosensitizing uridines. A larger activation barrier for DEA in BrSdU, as compared to ISdU, is probably responsible for the closure of DEA channel in the former system. Indeed, besides DEA, the XSdU anions may undergo competitive protonation, which makes the release of X - kinetically forbidden.

Although improvements in radiation therapy were made over the years, radioresistance is still a major challenge. Cancer cells are often deficient for DNA repair response, a feature that is currently exploited as a new anti-cancer strategy. In this context, combination of inhibitors targeting complementary pathways is of interest to sensitize cells to radiation. In this work, we used PARP (Olaparib) and RAD51 (B02) inhibitors to radiosensitize cancer cells to proton and X-ray radiation. More particularly, Olaparib and B02 were used at concentration leading to limited cytotoxic (alone or in combination) but increasing cell death when the cells were irradiated. We showed that, although at limited concentration, Olaparib and B02 were able to radiosensitize different cancer cell lines, i.e. lung and pancreatic cancer cells. Antagonistic, additive or synergistic effects were observed and correlated to cell proliferation rate. The inhibitors enhanced persistent DNA damage, delayed apoptosis, prolonged cell cycle arrest and senescence upon irradiation. These results demonstrated that radiation-induced synthetic lethality might widen the therapeutic window, hence extending the use of PARP inhibitors to patients without BRCAness.