Radiosensitizing Effect Research Articles

Abstract P009: Gadolinium-based nanoparticles sensitize ovarian peritoneal carcinomatosis to targeted radionuclide therapy

Abstract In 2024, around 13,000 women are expected to die from Ovarian Cancer (OC) in the US. Masked disease progression leads to late-stage diagnosis after the disease has spread to the peritoneal cavity (peritoneal carcinomatosis, PC). Treatments do not show substantial curative benefits, as disease will reoccur in 70-90% of patients. Targeted Radionuclide Therapy (TRT) specifically irradiates tumors sparing the surrounding healthy tissues, offering an attractive therapeutic option for metastatic spread. Here, we investigated the radiosensitizing effects of Gadolinium-based nanoparticles (Gd-NPs) combined with [177Lu]Lu-DOTA-trastuzumab. [177Lu]Lu-DOTA-trastuzumab injected activity (IA) combined or not with Gd-NPs was investigated in athymic female mice bearing intraperitoneal (IP) SKOV3 HER2+ tumor xenografts. The therapeutic efficacy and toxicity of 5 MBq [177Lu]Lu-DOTA-trastuzumab with Gd-NPs administered in different fractionated regimens were evaluated. NaCl, trastuzumab plus Gd-NPs and [177Lu]Lu-DOTA-trastuzumab were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Gd-NPs’ subcellular localization and uptake, cytotoxic effects of the combination and underlying radiosensitization mechanisms were investigated in 3 OC cell lines (SKOV3, OVCAR3, A431). Optimal therapeutic response was obtained with 2 injections of 5 mg Gd-NPs at 24 and 72 h after injection of [177Lu]Lu-DOTA-trastuzumab. The combination delayed tumor growth and significantly increased mice's median survival compared to all controls. SPECT/CT imaging on recovered tumor nodules highlighted specific targeting of both compounds after IP injection. In vitro experiments support the preclinical data, showing increased cytotoxicity of the drug combination. Fluorescence and Transmission Electron Microscopy (TEM) imaging showed co-localization of the NPs with the lysosomal compartment. Combination with Gd-NPs increased Reactive Oxygen Species (ROS) production and lipid peroxidation, suggesting a potential role of ferroptosis in the NPs-mediated toxicity. Fewer lysosomes were observed associated with cytoplasmic pH decrease, suggesting lysosomal disruption. Cytoplasmic vacuolization, mitochondrial depolarization, apoptosis, and micronuclei formation were noted and reversed by iron chelation. Dosimetry calculations revealed that exposure of Gd-NPs to 177Lu increased the Auger electron yield, but not the absorbed dose. We provide strong evidence in vivo of Gd-NPs radiosensitizing effect when combined, for the first time, with a radiolabeled antibody. At a cellular level, we report a high dependence on iron-derived hydroxyl radical production, leading to a lysosomal–mediated cell disruption. The radiosensitization effect allows reduction of the IA in mice, keeping a high therapeutic efficacy while decreasing treatment-related toxicities. As Gd-NPs are already combined with EBRT in clinical trials, the present study opens perspectives to optimize and translate this theranostic strategy for the treatment of OC-derived PC. Citation Format: Clara Diaz Garcia-Prada, Lena Carmes, Ali Parach, Alejandro Bertolet, Sophie Poty, Jan Schuemann, Olivier Tillement, François Lux, Julie Constanzo, Jean-Pierre Pouget.Gadolinium-based nanoparticles sensitize ovarian peritoneal carcinomatosis to targeted radionuclide therapy.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P009

Abstract A010: PARP1 selective inhibition sensitize triple-negative breast cancers to photon and alpha-particle therapy regardless of homologous recombination proficiency status

Abstract The association of Poly (ADP-ribose) polymerase (PARP) inhibitors with radiotherapy (RT) increase RT-induced DNA damage and radiosensitize tumors regardless deficiency in DNA repair pathways. Although PARP1 is the main protein responsible for PARP-mediated DNA repair, all first-generation PARP inhibitors act on both PARP1 and PARP2, which the latter is associated with hematological toxicity. The RT ability to induce DNA damage can be influenced by the radiation linear energy transfer (LET). High-LET radiation, such as alpha particles (LET: 60-200 keV/μm), induces more complex DNA damage than does low-LET radiation (photon, LET: 0.2 keV/μm). Thus, high-LET radiation combined with selective PARP1 inhibitors may be a promising strategy to radiosensitize tumors. The purpose of this study was to investigate if the selective PARP1 inhibition could radiosensitize BRCA1 mutant and wild-type triple-negative breast cancers (TNBC) to photons and alpha particles. The radiosensitization effect in vitro was assessed using TNBC cells: MDA-MB-436 (BRCA1 mutated), and its isogenic pair with BRCA1 recovered, MDA-MB-436 BRCA1, and 4T1. The IC50 of the PARP1 selective inhibitor (AZD5305) was determined across all cell lines by the clonogenic assay, and concentrations of AZD5305 that did not affect the colony formation ability without radiation were chosen for the radiopotentiation evaluation (clonogenic assay). Mice were inoculated with 4T1 cells in the hind leg. Diffusing Alpha-emitter Radiation Therapy (Alpha DaRT) was used to deliver alpha particles intratumorally, by the implantation of 224Ra-loaded sources. AZD5305 (1 mg/kg) was daily administered by oral gavage for 6 consecutive days, starting 24 h before Alpha DaRT implantation. Tumor growth delay and survival were assessed. AZD5305 significantly radiosensitized all the evaluated cell lines in vitro. AZD5305 alone (mice implanted with inert seeds) did not affect the tumor growth in mice (p=0.12) in comparison with inert+vehicle. Alpha DaRT delayed tumor growth in comparison with mice treated with inert+vehicle (p=0.03), but the Alpha DaRT+AZD5305 reduced tumor growth in comparison with Alpha DaRT+vehicle (p=0.05). Alpha DaRT promoted a non-significant (p=0.09) increase in survival when compared with inert+vehicle, but Alpha DaRT+AZD5305 increased survival in comparison with inert+vehicle (p=0.002), and Alpha DaRT+vehicle (p=0.06). Our findings demonstrate that AZD5305 significantly radiosensitizes TNBC to photons and alpha particles, regardless of the homologous recombination proficiency status. These results are novel because there no studies investigating selective PARP1 inhibition in combination with photons and alpha particles. Our work is relevant because the combination of AZD5305 with Alpha DaRT offers a promising strategy to minimize the adverse effects of PARP inhibition. AZD5305 presents less off-target effects than non-selective PARP inhibitors, while Alpha DaRT delivers alpha particles directly into the tumor, limiting radiosensitization of normal tissue. Citation Format: Poliana C. Marinello, Marco Tulio Freitas Reis, Walison Augusto Da Silva Brito, Amy Wu, Alexandre Rubinstein, Mark D. Wasley, Mandira Manandhar, Scott J. Bright, Yogesh Rai, Seyed Mojtaba Hosseini Ghahfarokhi, Ronen Segal, Vered Domankevich, Gabriel O. Sawakuchi. PARP1 selective inhibition sensitize triple-negative breast cancers to photon and alpha-particle therapy regardless of homologous recombination proficiency status. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A010.

Radiosensitization of Rare-Earth Nanoparticles Based on the Consistency Between Its K-Edge and the X-Ray Bremsstrahlung Peak

Nanoparticle-based X-ray radiosensitization strategies have garnered significant attention in recent years. However, the underlying mechanisms of radiosensitization remain incompletely understood. In this work, we explore the influence of the K-edge effect in the X-ray absorption of nanomaterials on sensitization. Due to the alignment of the K-edge of thulium (Tm) with the Bremsstrahlung peak in the energy spectrum of medical X-ray accelerators, the following four different rare-earth nanomaterials with varying Tm percentages were designed: NaTmF4, NaTm0.6Lu0.4F4, NaTm0.4Lu0.6F4, and NaLuF4. We evaluated the X-ray absorption and the ability to generate secondary electrons and reactive oxygen species (ROS) of these nanoparticles. The radiosensitizing effect was evaluated through clonogenic assays. Our results showed that the K-edge effect affected secondary electron generation but did not significantly change ROS production. Nonetheless, NaTmF4 induced marginally more DNA damage in the U87 cells than the other cell types. NaTmF4 also exhibited superior radiosensitization efficacy against the U87 tumor cells. This shows that secondary electrons and ROS play pivotal roles in radiosensitization, which might be crucial to improving cancer treatment efficacy through enhanced radiation therapy outcomes.

Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models.

Mutations in the KRAS oncogene can mediate resistance to radiation. KRAS mutation (mut) driven tumors have been reported to express cancer stem cell (CSC)-like features and may harbor metabolic liabilities through which CSC-associated radioresistance can be overcome. We established a radiation/drug screening approach that relies on the growth of 3D spheres under anchorage-independent and lipid-limiting culture conditions, which promote stemness and lipogenesis. In this format, we screened 32 KRASmut-enriched lung cancer models. As predicted from published data, CB-839, a glutaminase inhibitor, displayed the highest degree of radiosensitization in KRASmut models with LKB1 co-mutations. Radiosensitization by inhibition of stearoyl-CoA desaturase-1, SCD1, displayed a similar genotype preference though the data also implicated KEAP1 co-mutation and SCD1 expression as potential predictors of radiosensitization. In an isogenic model, KRASmut cells were characterized by increased SCD1 expression and a higher ratio of monounsaturated fatty acids (MUFA) to saturated fatty acids. Accordingly, pharmacological inhibition or depletion of SCD1 radiosensitized isogenic KRASmut but not wild-type cells. The radiosensitizing effect was notably small, especially compared to several DNA repair inhibitors. As an alternative strategy to targeting MUFA metabolism, adding polyunsaturated FAs (PUFA) phenocopied some aspects of SCD1 inhibition, suppressed tumor growth in vivo, and opposed the CSC-like phenotype of KRASmut cells. In conclusion, we report a 3D screening approach that recapitulates clinically relevant features of KRASmut tumors and can be leveraged for therapeutic targeting of metabolic vulnerabilities. Our data highlight pronounced inter-tumoral heterogeneity in radiation/drug responses and the complexity of underlying genomic dependencies.

Revolutionizing radiotherapy: gold nanoparticles with polyphenol coating as novel enhancers in breast cancer cells—an in vitro study

Breast cancer is the most common cancer among women, with over 1 million new cases and around 400,000 deaths annually worldwide. This makes it a significant and costly global health challenge. Standard treatments like chemotherapy and radiotherapy, often used after mastectomy, show varying effectiveness based on the cancer subtype. Combining these treatments can improve outcomes, though radiotherapy faces limitations such as radiation resistance and low selectivity for malignant cells. Nanotechnologies, especially metallic nanoparticles (NPs), hold promise for enhancing radiotherapy. Gold nanoparticles (AuNPs) are particularly notable due to their high atomic number, which enhances radiation damage through the photoelectric effect. Studies shown that AuNPs can act as effective radiosensitizers, improving tumor damage during radiotherapy increasing the local radiation dose delivered. Traditional AuNPs synthesis methods involve harmful chemicals and extreme conditions, posing health risks. Green synthesis methods using plant extracts offer a safer and more environmentally friendly alternative. This study investigates the synthesis of AuNPs using Laurus nobilis leaf extract and their potential as radiosensitizers in breast carcinoma cell lines (MCF-7). These cells were exposed to varying doses of X-ray irradiation, and the study assessed cell viability, morphological changes and DNA damage. The results showed that green-synthesized AuNPs significantly enhanced the therapeutic effects of radiotherapy at lower radiation doses, indicating their potential as a valuable addition to breast cancer treatment.

Viability and Radiosensitivity of Human Tumor Cells from Breast and Colon Are Influenced by Hypericum perforatum Extract HP01.

To enhance the treatment of tumors that are resistant to radio- and chemotherapy while minimizing the side effects of radiochemotherapy, researchers are continuously seeking new active compounds for use in combination with radiotherapy. Therefore, the aim of our study was to examine the cytotoxic and radiosensitizing effects of an extract from St. John's Wort (Hypericum perforatum), referred to as HP01, on human epithelial tumor cells in vitro. The growth of MCF-7 (breast carcinoma) and HT-29 (colon carcinoma) cells was examined under the influence of HP01. In combination with radiation, the effects of HP01 on cytotoxicity and long-term survival were assessed using a colony formation assay. The number of DNA double-strand breaks was analyzed using the γH2AX assay, while cell cycle distribution was examined via flow cytometry. A growth-inhibiting and cytotoxic effect was observed for both tumor cell lines starting at a concentration of 10 µg/mL HP01. Treatment with HP01 resulted in an inhibition of clonogenic survival of tumor cells after ionizing radiation (6 Gy). The number of DNA double-strand breaks (DSBs) in tumor cells increased with HP01 treatment, but the repair of radiation-induced DNA DSBs was not affected. Cell cycle analysis revealed that HP01, in addition to radiation, enhanced G2/M arrest in MCF-7 and HT-29 cells. Overall, HP01 not only showed a growth-inhibiting effect but also demonstrated a radiosensitizing effect on human tumor cells for the first time. We conclude that the HP01-induced G2/M accumulation of cells may be the main rationale for the drug-induced radiosensitivity. It is therefore a promising candidate for combined therapy in tumor diseases and warrants further investigation.

Impact of gold nanoparticle size and coating on radiosensitization and generation of reactive oxygen species in cancer therapy.

Radiation therapy is a common cancer treatment but often damages surrounding healthy tissues, leading to unwanted side effects. Despite technological advancements aimed at improving targeting, minimizing exposure to normal cells remains a major challenge. High-Z nanoparticles, such as gold nanoparticles (AuNPs), are being explored as nano-radiosensitizers to enhance cancer treatment through physical, biological, and chemical mechanisms. This study focuses on evaluating the chemical and biological radiosensitizing effects of AuNPs exposed to ionizing radiation (0-50 Gy), specifically their production of reactive oxygen species (ROS) and their impact on cancer cells. ROS generated by AuNPs of varying sizes and coatings were quantified using fluorescence probes for hydroxyl radicals (HO·) and singlet oxygen (1O2). The radiosensitizing effects on MDA-MB-231 cancer cells were assessed via clonogenic assays. Our results show a clear dependence of ROS production on AuNP size. Interestingly, PEG-capped AuNPs did not significantly enhance HO· production but greatly increased 1O2 production, suggesting that multiple reactive species contribute to the radiosensitization process. Clonogenic assays confirmed that PEG-capped AuNPs produced stronger radiosensitizing effects than citrate-capped AuNPs, with smaller AuNPs providing more pronounced biological effects. This study underscores the importance of conducting both chemical and biological evaluations to fully understand the radiosensitization efficacy of AuNPs.

Ionizing Radiation Combined with Gold Complex Compounds Causes Apoptosis in Colorectal Cancer Cells by Increasing the Level of Caspase-3.

The anticancer activity and radiosensitizing effect of Auranofin, an an-tirheumatic and an approved gold metallic drug, have been investigated from multiple perspectives. In this study, the action of the new gold complex compound TPN-Au(I)-MM4 was compared with that of auranofin. The inhibitory effect of 10 μM and 50 μM concentrations on cell proliferation was investigated using the human colon cancer cell lines HCT116 and SW480. The radiosensitizing effect of HCT116 cells was evaluated by measuring the ability to induce apoptotic cell death. The mechanism of action was qualitatively determined via western blotting analysis of the level of cleaved caspase-3 protein. Auranofin completely inhibited cell proliferation in both cell lines at both concentrations. In contrast, only 50 μM of TPN-Au(I)-MM4 significantly inhibited the proliferation of SW480 cells, but did not affect the proliferation of HCT116 cells. On the other hand, both compounds effectively increased the apoptotic cell death rate when combined with 4 Gy of X-ray irradiation. This mechanism was caused by a significant increase in the level of caspase-3, which is an apoptosis execution factor, by the combination of these two treatments. Both compounds promoted the significant expression of caspase-3, an apoptosis execution factor, and exhibited radio-sensitizing effects. In particular, TPNAu( I)-MM4 showed no inhibitory effect on cell proliferation alone, but had a significant radiosensitising effect on HCT116 cells. Therefore, TPN-Au(I)-MM4 has the potential for use as a new radiosensitizer.

Sulforaphane Induces Transient Reactive Oxygen Species-Mediated DNA Damage in HeLa Cells.

Sulforaphane (SFN), an isothiocyanate found in plants of the Brassicaceae family, possesses antioxidant, apoptosis-inducing, and radiosensitizing effects. As one of the mechanisms of cytotoxicity by SFN, SFN has been suggested to be involved in the induction of DNA damage and inhibition of DNA repair. Recently, we reported on the potency of SFN in inducing single-ended double-strand breaks (DSBs) that are caused by the collision of replication forks with single-strand breaks (SSBs). However, the mechanism of SSB accumulation by SFN remains unclear. In this study, we examined the effect of SFN on SSB-inducing factors in HeLa cells. Although the inhibitory effect of SFN on DNA topoisomerase I was not observed, we found that the reduced form of glutathione (GSH; an antioxidant) level was decreased in an SFN concentration-dependent manner. Furthermore, the addition of ascorbic acid partially increased the viability of SFN-treated HeLa cells. We subsequently observed that poly(ADP-ribose) accumulated in SFN-treated HeLa cells, which occurs during early SSB repair. Collectively, these findings suggest that SFN may transiently induce SSBs via reactive oxygen species in HeLa cells.

Indium(iii) complexes with Schiff base-derived polydentate ligands: chemotherapeutic, radiochemotherapeutic, and radiosensitizer potentials against breast tumor cells

In(iii) and 114mIn(iii) complexes with polydentate Schiff base-derived ligands showed cytotoxic activity against MCF-7 and MDA-MB-231 breast tumor cells. The In(iii) complexes presented radiosensitizer effects, improving the efficacy of radiotherapy.

Locked Dimerized CXCL12 Exerts Radiosensitizing Effects in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) presents significant treatment challenges, particularly in cases unrelated to human papillomavirus (HPV). The chemokine receptor CXCR4, interacting with its ligand CXCL12, plays a crucial role in tumor proliferation, metastasis, and treatment resistance. This study explores the therapeutic potential of engineered monomeric and dimerized CXCL12 variants (CXCL121 and CXCL122, respectively) in HNSCC and evaluates potential additive effects when combined with radiation therapy. Clinical HNSCC biopsies were evaluated for CXCR4 expression in both previously untreated and radiorecurrent disease. HNSCC cell lines were then treated with combinations of CXCL12 variants and radiotherapy and interrogated for proliferation, gene expression change, and underlying molecular mechanisms. Invivo studies evaluated the biodistribution of engineered CXCL12 and tested these treatments in humanized cell line-derived xenograft (CDX) models. CXCL122 significantly reduced HNSCC cell proliferation and enhanced the effects of radiotherapy, likely through biased agonism at the CXCR4 receptor and upregulation of the KISS1R pathway. Invivo, CXCL122 localized to tumor sites and augmented the effects of radiation to inhibit tumor growth. CXCL122, in combination with radiation, demonstrates potent anti-tumor effects in HNSCC. These findings support further clinical investigation of CXCL122 to enhance the effects of radiotherapy.

Radiosensitization impact assessment of silica-layered iron oxide nanocomposites with various shell thickness.

Silica shell is considered to be a promising design that enhances nanocomposite stability, cellular internalization, and consequentially therapeutic impacts by overcoming their aggregation under physiological conditions. This study addressed synthesizing silica-layered iron oxide-based nanoparticles (SCINPs) with different shell thicknesses (1-SCINPs, 2-SCINPs, 3-SCINPs, and 4-SCINPs). Also, the impact of shell thickness on the nanoparticle's cellular internalization and the radio-sensitizing effect of prepared nano-formulations were assessed. The physical properties of the synthesized nanoparticles were examined using transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), vibrating sample magnetometry (VSM), and X-ray diffraction (XRD). Cytotoxicity assay, oxidative stress parameters, and comet assay were used to investigate the radio-sensitizing effect of various nanoformulations. Results revealed that the mean diameter of prepared oxide-based nanoparticles (INPs) was about 12.63±1.36nm, and the shell thickness for 1-SCINPs, 2-SCINPs, 3-SCINPs, and 4-SCINPs was 22.58±3.51, 26.13±1.40, 46.95±3.10 and 60.30±4.30nm, respectively. Interestingly, we found that in cells treated with 40μg/ml of INPs, their viability decreased to 44.6%. Meanwhile, the viability was 41.69% and 39.4% for cells treated with 1-SCINPs and 2-SCINPs, respectively. This means that a thicker silica shell led to a decreased impact on radiosensitization. This was attributed to the influence of surface properties and size of SCINPs on their cellular uptake and the secondary electrons' entrapment within thicker shells upon radiation exposure. Cell viability test, comet assay and oxidative stress parameters show that 2-SCINPs formulations had the most potent radiosensitizing effect (with the highest dose enhancement factor equal to 2.1) when combined with radio-treatment. The results suggest that optimizing the silica shell thickness is critical for maximizing the therapeutic efficacy of SCINPs, with 2-SCINPs showing the highest radiosensitization effect.

Novel Flavin Mononucleotide-Functionalized Cerium Fluoride Nanoparticles for Selective Enhanced X-Ray-Induced Photodynamic Therapy.

X-ray-induced photodynamic therapy (X-PDT) represents a promising new method of cancer treatment. A novel type of nanoscintillator based on cerium fluoride (CeF3) nanoparticles (NPs) modified with flavin mononucleotide (FMN) has been proposed. A method for synthesizing CeF3-FMN NPs has been developed, enabling the production of colloidal, spherical NPs with an approximate diameter of 100 nm, low polydispersity, and a high fluorescence quantum yield of 0.42. It has been demonstrated that CeF3-FMN NPs exhibit pH-dependent radiation-induced redox activity when exposed to X-rays. This activity results in the generation of reactive oxygen species, which is associated with the scintillation properties of cerium and the transfer of electrons to FMN. The synthesized NPs have been demonstrated to exhibit minimal cytotoxicity towards normal cells (NCTC L929 fibroblasts) but are more toxic to tumor cells (epidermoid carcinoma A431). Concurrently, the synthesized NPs (CeF3 and CeF3-FMN NPs) demonstrate a pronounced selective radiosensitizing effect on tumor cells at concentrations of 10-7 and 10-3 M, resulting in a significant reduction in their clonogenic activity, increasing radiosensitivity for cancer cells by 1.9 times following X-ray irradiation at a dose of 3 to 6 Gy. In the context of normal cells, these nanoparticles serve the function of antioxidants, maintaining a high level of clonogenic activity. Functional nanoscintillators on the basis of cerium fluoride can be used as part of the latest technologies for the treatment of tumors within the framework of X-PDT.

The Combined Effect of Hypoxia Activation and Radiosensitization by a Multifunctional Nanoplatform System Enhances the Therapeutic Efficacy of Chemoradiotherapy in Pancreatic Cancer

BackgroundPancreatic cancer is a highly malignant tumor, which is still a major global health problem. Chemotherapy and radiotherapy are regularly used in adjuvant therapy for pancreatic cancer but their therapeutic efficacy is limited. MethodsIn the present study, nanoparticle（MSN-AuNPs） was used as a drug carrier loaded with tirapazamine(TPZ) and hyaluronic acid (HA) to synthesize a multifunctional nanoplatform HA@TPZ-MSN-AuNPs (HTMA) for hypoxia activation and radiotherapy sensitization, which can be combined with radiotherapy therapy and synergistically enhance the therapeutic effect in pancreatic cancer. The anti-tumor performance of the nano platform was verified by in vivo and in vitro experiments. ResultFirst, the HA@TPZ-MSN-AuNPs (HTMA) was successfully synthesized. Drug release experiments showed that acidic environment and hyaluronidase promoted drug release in the nanoplatform. In vitro experiments, CCK-8, live-dead staining, clonal formation assay and flow cytometry confirmed the combined anti-tumor effect of hypoxia activation and radiotherapy sensitization with HTMA. In the drug uptake experiment, the nanoplatform showed the function of targeting and binding pancreatic cancer cells. In vivo, HTMA demonstrated good antitumor properties and good biocompatibility. ConclusionsThe nanoplatform had a good targeting effect and synergistic anti-tumor effect. The combination of hypoxia activation and radiotherapy sensitization is a promising strategy for the treatment of pancreatic cancer.

RSL3 sensitizes glioma cells to ionizing radiation by suppressing TGM2-dependent DNA damage repair and epithelial-mesenchymal transition.

RAS-selective lethal small molecule 3 (RSL3) is a small-molecule compound that triggers ferroptosis by inactivating glutathione peroxidase 4. However, its effect on the radioresistance of glioma cells and the underlying mechanisms remains unclear. In this study, we found that RSL3 sensitized glioma cells to ionizing radiation (IR) and enhanced IR-induced DNA double-strand breaks (DSBs). Inhibition of ferroptosis pathways partly prevented the clonogenic death caused by the IR/RSL3 combination but did not alleviate the DNA DSBs, indicating that RSL3 promotes IR-induced DNA DSBs via a non-ferroptotic mechanism. We demonstrated that transglutaminase 2 (TGM2) plays a vital role in the radiosensitization effect of RSL3 on glioma cells. Treatment with RSL3 downregulated TGM2 in a dose-dependent manner. Overexpression of TGM2 not only alleviated DNA DSBs but also inhibited clonogenic death caused by the IR/RSL3 combination. Mechanistically, RSL3 triggered oxidative stress in glioma cells, which promoted the S-gluthathionylation of TGM2 via upregulation of glutathione S-transferase P1(GSTP1), culminating in the proteasomal degradation of TGM2. This process resulted in the suppression of DNA repair mechanisms by impeding the nuclear accumulation of TGM2 and disrupting the interaction between TGM2 and topoisomerase IIα after irradiation. We also found that RSL3 inhibited glioma cell epithelial-mesenchymal transition (EMT) in both IR-treated and non-IR-treated cells. Overexpression of TGM2 prevented, while knockdown of TGM2 aggravated the EMT inhibition caused by RSL3, indicating that RSL3 also sensitized glioma cells to IR by inhibiting EMT via a TGM2-dependent mechanism. Furthermore, in mice bearing human U87 tumor xenografts, RSL3 administration synergized with IR to inhibit tumor growth, accompanied by TGM2 inhibition, DNA DSBs, and EMT inhibition in tumor tissues. Taken together, we demonstrated that RSL3 sensitizes glioma cells to IR by suppressing TGM2-mediated DNA repair and EMT.

Persistent luminescent nanoprobes with dual effect radiosensitization for precise radiotherapy

Radiotherapy (RT) is a common modality in the clinical management of breast cancer. However, the radiation damage to healthy tissues caused by the high-dose radiation and the limited therapeutic efficacy with DNA damage repair pose significant challenges in RT. In this work, an intelligent responsive nanoplatform with dual effect radiosensitization (mZGSSM-AMD) has been developed to improve the efficacy of RT. The doping of Lu promotes the generation of reactive oxygen species (ROS) under X-ray irradiation, thereby facilitating DNA breakage. To hinder the repair of damaged DNA, NO is loaded into mZGSSM-AMD, enhancing damage of tumor during radiotherapy. Furthermore, persistent luminescence (PersL) recovers with the degradation of MnO2 in tumor microenvironment (TME), which guides precision radiosensitization of tumors. Experimental results indicate that growth of tumors is significantly suppressed by effective radiosensitization of mZGSSM-AMD. The mZGSSM-AMD with dual effect radiosensitization exhibits exceptional antitumor effectiveness, providing promising application prospects for the imaging-guided precise radiosensitization therapy.

The potential of HSA-stabilized zinc oxide nanoparticles as radiosensitizers to enhance the cytotoxic effects and radiosensitivity of cervical cancer cells

BackgroundCervical cancer is a significant cause of death among women worldwide, and limited treatment approaches are available for patients with metastatic or recurrent disease. Recently, the combination of nanoparticles (NPs) and radiotherapy (RT) has been shown to be an effective treatment because it enhances the sensitivity of cancer cells to radiation. ZnO NPs stabilized with HSA have become one of the most popular types of metal oxide nanoparticles because of their cost-effectiveness and minimal toxicity. Therefore, our study aimed to investigate the radiosensitization effects of HSA/ZnO-NPs on cervical (HeLa) cancer cells under megavoltage (MV) X-ray irradiation.MethodsHSA/ZnO-NPs were prepared and characterized by SEM and Dynamic Light Scattering (DLS) technique. The cytotoxicity of HSA/ZnO NPs was evaluated in HeLa cells via an MTT assay. The radiosensitization effects were investigated under megavoltage X-ray irradiation using a clonogenic survival assay and quantifying γH2AX foci. Moreover, apoptosis and cell cycle analyses were conducted using a Muse™ Cell Analyzer.ResultsHSA/ZnO-NPs reduced the viability of HeLa cells in a dose-dependent manner, which revealed that the IC50 of HSA/ZnO-NPs was approximately 30 µg/mL. The prepared particles exhibited moderate aggregation regarding hydrodynamic size (approximately 300–400 nm) and a negative zeta potential charge. Compared to the control group, combining HSA/ZnO-NPs with irradiation reduced the colony-forming ability and survival of HeLa cells by approximately 51% and 71% for 2 and 4 Gy, respectively. Correspondingly, the results of the apoptosis analysis showed that combining HSA/ZnO-NPs with irradiation significantly increased apoptosis induction by approximately 39.15% and 77.67% for 2 and 4 Gy, respectively. In addition, we observed a significant increase in cell cycle arrest at the S phase, by about 11.3% and 19.3% for 2 and 4 Gy, respectively.ConclusionsHSA/ZnO-NPs could significantly enhance the cytotoxic effects of ionizing radiation, which suggests the promising potential of cervical cancer radiotherapy under megavoltage X-ray irradiation.

Effects of a novel HDAC6-selective inhibitor's radiosensitization on cancer cells.

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. 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. 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. 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.

Olaparib enhancing radiosensitization and anti-metastatic effect of oral cancer by targeting IL-17A signal

PurposeWe tested whether the PARP inhibitor, Olaparib, can effectively enhance radiosensitivity while inhibiting OSCC growth and metastasis in vitro and in vivo. Patient samples were used for survival validation.MethodsThe present study investigated the effect of Olaparib and ionizing radiation (IR) on clonogenic, migratory, and invasive ability in human IR-sensitive (OML1) and IR-resistant (OML1-R) OSCC cell lines. We next explored the underlying mechanism with ELISA and a Western blotting assay. Two in vivo mouse models were established to investigate the efficacy of Olaparib combined with radiotherapy (RT) on local tumor growth and lung metastasis. IL-17 A expression was confirmed in tissue specimens of OSCC patients by immunohistochemistry.ResultsWe found that Olaparib, in combination with IR, substantially inhibited cell growth, migration, and invasion in vitro. Mechanistically, the Olaparib treatment significantly reduced the secretion of IL-17 A in irradiated OSCC cells by attenuating NF-κB and p38 activity. Consistently, Olaparib enhanced the radiosensitivity and, with RT, synergistically reduced both tumor growth and lung metastasis in mice. In addition, OSCC patients with high IL-17 A expression were substantially associated with an increased risk of lymph node involvement and worse survival.ConclusionsThis study has highlighted that Olaparib displays radiosensitizing and antimetastatic effects by inhibiting the IL-17 A-dependent signal. Remarkably, Olaparib could provide a remarkable anticancer efficacy to improve treatment response in OSCC patients with recurrent/metastatic disease after RT.

Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer

We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.