Search Results (163)

Breast-conserving surgery followed by external beam Radiotherapy (RT) is a standard approach for early-stage Breast Cancer (BC). This retrospective study aims to determine the risk of RT-induced lung cancer for both standard and hypofractionated treatments. Fifty-eight Sicilian women treated at Humanitas Istituto Clinico Catanese (Misterbianco, Italy) between 2015 and 2021 with standard fractionated 3D-CRT (50 Gy in 2 Gy/fraction) were included. All treatment plans were designed using a hypofractionated schedule (42.56 Gy in 2.66 Gy/fraction). An Eclipse™ plug-in script was developed using the Eclipse Scripting Application Programming Interface (ESAPI) to extract patient and treatment data from the Treatment Planning System and compute Organ At Risk (OAR) volume, Organ Equivalent Dose (OED), Excess Absolute Risk (EAR), and Lifetime Attributable Risk (LAR) using the Schneider Mechanistic Model and reference data from regional populations, A-bomb survivors, and patients with Hodgkin’s Disease (HD). The OED distributions exhibited a statistically significant shift toward higher values in standard fractionated plans (p < 0.01, one-tailed paired Student’s t-test), leading to increased EAR and LAR. These results indicate that hypofractionated treatment may lower the risk of radiation-induced lung cancer. The feasibility of a priori risk estimation was evaluated by integrating the script into the TPS, allowing rapid comparison of SF and HF plans during planning. Full article

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction between RT and the complement system as a possible approach to improve immune responses in cancer treatment. Methods: Human solid cancer (lung, prostate, liver, breast cancer), lymphoma, and leukemia cells were irradiated using X-rays and treated with polyclonal antibodies or anti-CD20 monoclonal antibodies, respectively. Chromium release assay was applied to measure cell lysis after radiation with or without complement-activating antibody treatment. The expression of membrane-bound complement regulatory proteins (mCRPs; CD46, CD55, CD59), which confer resistance against complement activation, CD20 expression, apoptosis, and radiation-induced DNA double-strand breaks (γH2AX), was measured by flow cytometry. The radiosensitivity of tumor cells was assessed by colony-forming assay. Results: We demonstrate that RT profoundly impacts complement function by upregulating the expression of membrane-bound complement regulatory proteins (mCRPs) on tumor cells in a dose- and time-dependent manner. Impaired complement-mediated tumor cell lysis could thus potentially contribute to radiotherapeutic resistance. We also observed RT-induced upregulation of CD20 expression on lymphoma and leukemic cells. Notably, complement activation prior to RT proved more effective in inducing RT-dependent early apoptosis compared to post-irradiation treatment. While complement modulation does not significantly alter RT-induced DNA-damage repair mechanisms or intrinsic radiosensitivity in cancer cells, our results suggest that combining RT with complement-based anti-cancer therapy may enhance complement-dependent cytotoxicity (CDC) and apoptosis in tumor cells. Conclusions: This study sheds light on the complex interplay between RT and the complement system, offering insights into potential novel combinatorial therapeutic strategies and a potential sequential structure for certain tumor types. Full article

Long noncoding RNAs (lncRNAs), non-protein-coding transcripts exceeding 200 nucleotides, are critical regulators of gene expression through chromatin remodeling, transcriptional modulation, and post-transcriptional modifications. While ionizing radiation (IR) induces cellular damage through direct DNA breaks, reactive oxygen species (ROS)-mediated oxidative stress, and bystander effects, the functional involvement of lncRNAs in the radiation response remains incompletely characterized. Here, through genome-wide CRISPR activation (CRISPRa) screening in non-small cell lung cancer (NSCLC) cells, we identified LOC401312 as a novel radiosensitizing lncRNA, the stable overexpression of which significantly enhanced IR sensitivity. Transcriptomic profiling revealed that LOC401312 transcriptionally upregulates carbamoyl-phosphate synthase 1 (CPS1), a mitochondrial enzyme involved in pyrimidine biosynthesis. Notably, CPS1 overexpression recapitulated the radiosensitization phenotype observed with LOC401312 activation. Mechanistic investigations revealed that CPS1 suppresses the phosphorylation of ATM kinase (Ser1981) protein, which is a key mediator of DNA damage checkpoint activation. This study established the LOC401312–CPS1–ATM axis as a previously unrecognized regulatory network governing radiation sensitivity, highlighting the potential of lncRNA-directed metabolic rewiring to impair DNA repair fidelity. Our findings not only expand the functional landscape of lncRNAs in DNA damage response but also provide a therapeutic rationale for targeting the LOC401312–CPS1 axis to improve radiotherapy efficacy in NSCLC. Full article

Background/Objectives: The PACIFIC trial showed that immune checkpoint inhibitors (ICI) administered after concurrent chemoradiotherapy (cCRT) significantly improve survival in stage III unresectable non-small cell lung cancer (NSCLC). However, the optimal timing of ICI administration with cCRT is still debated, with concerns about increased risks of adverse effects, particularly radiation-induced pneumonitis (RP), from combining radiotherapy and immunotherapy. Methods: A search of multiple databases identified studies on stage III unresectable NSCLC patients receiving cCRT and ICI. A meta-analysis was performed utilizing the meta package in R software. Furthermore, data from 170 patients treated at Shandong Cancer Hospital and Institute between 2019 and 2023 were analyzed to assess RP following cCRT and ICI treatment. Results: The meta-analysis revealed that the incidences of ≥grade 2 RP were 25.3%, 24.3%, and 45.3% in the ICI following cCRT group, the ICI concurrent with cCRT group, and the ICI prior to cCRT group, respectively. The ICI prior to cCRT group exhibited significantly elevated rates. In the clinical retrospective study, ≥grade 2 RP was more prevalent in the ICI concurrent with cCRT group (HR: 2.258, 95% CI: 1.135–4.492, p = 0.020) and the ICI prior to cCRT group (HR: 2.843, 95% CI: 1.453–5.561, p = 0.002) compared with the ICI following cCRT group. Furthermore, a shorter interval between treatments correlates with an increased incidence of RP. Conclusions: Advancing the timing of ICI administration is associated with an increased incidence of ≥grade 2 RP following cCRT in patients with stage III unresectable NSCLC. Full article

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potential therapeutic for cancer patients due to its tumor specificity. However, TRAIL resistance in cancer cells limits its development in clinical trials. Given that ionizing radiation (IR) is an established method of inducing DNA damage for cancer during radiotherapy, we applied a combined treatment of IR and TRAIL. Our study shows that the combination treatment of IR and TRAIL promoted cell death due to IR upregulating both DR4/DR5 receptors on the surface of human lung carcinoma cell line H460 and human colon cancer cell line DLD-1 2D cells. However, when cultured as 3D spheroids, we observed that IR enhanced DR5-specific TRAIL-induced cell death but attenuated DR4-specific TRAIL-induced cell death. The immunohistochemical analysis of 3D cell spheroid sections indicates that it is due to a lack of DR4 overexpression by IR. Our findings elucidate a potential explanation for the failure of the combination treatment of radiotherapy with TRAIL in clinical trials. Additionally, our findings advocate the potential efficacy of employing DR5-specific TRAIL in combination with radiation as a promising therapeutic strategy. Full article

Radon is an inert gas produced by the radioactive decay of uranium-238, commonly found in the environment. Radon and its decay products are the main sources of human exposure to radiation from natural sources. When inhaled, radon’s alpha particles impact lung tissue, potentially causing lung cancer by damaging DNA and altering oxidative processes. This review article addresses the need for a deeper understanding of the genetic and molecular changes associated with radon-induced lung cancer, aiming to clarify key genetic mutations and protein markers linked to carcinogenesis. Particular attention in recent studies has been given to mutations in tumor suppressor genes (RASSF1, TP53), oncogenes (KRAS, EGFR), and changes in the expression levels of protein biomarkers associated with inflammation, stress, and apoptosis. Identifying these markers is critical for developing effective screening methods for radon-induced lung cancer, enabling timely identification of high-risk patients and supporting effective preventive strategies. Summarizing current genetic and protein biomarkers, this review highlights the importance of a comprehensive approach to studying radon-induced carcinogenesis. Understanding these molecular mechanisms could ultimately improve early diagnostic methods and enhance therapy for cancers associated with radon exposure. Full article

Background: Radioresistance remains a significant obstacle in lung cancer radiotherapy, necessitating novel strategies to enhance therapeutic efficacy. This study investigated the radiosensitizing potential of a soybean lecithin–gallic acid complex (SL–GAC) in non-small cell lung cancer (NSCLC) cells and explored its underlying ferroptosis-related mechanisms. SL–GAC was synthesized to improve the bioavailability of gallic acid (GA), a polyphenol with anticancer properties. Methods: NSCLC cell lines (A549 and H1299) and normal bronchial epithelial cells (BEAS-2B) were treated with SL–GAC, ionizing radiation (IR), or their combination. Through a series of in vitro experiments, including cell viability assays, scratch healing assays, flow cytometry, and Western blot analysis, we comprehensively evaluated the effects of SL-GAC on NSCLC cell proliferation, migration, oxidative stress, and ferroptosis induction. Results: SL–GAC combined with IR synergistically suppressed NSCLC cell proliferation and migration, exacerbated oxidative stress via elevated ROS and malondialdehyde levels, and induced mitochondrial dysfunction marked by reduced membrane potential and structural damage, whereas no significant ROS elevation was observed in BEAS-2B cells. Mechanistically, the combination triggered ferroptosis in NSCLC cells, evidenced by iron accumulation and downregulation of Nrf2, SLC7A11, and GPX4, alongside upregulated ACSL4. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, reversed these effects and restored radiosensitivity. Conclusions: Our findings demonstrate that SL–GAC enhances NSCLC radiosensitivity by promoting ferroptosis via the Nrf2/SLC7A11/GPX4 axis, highlighting its potential as a natural radiosensitizer for clinical translation. Full article

Growth hormone-releasing hormone (GHRH) antagonists exert antitumor functions in different experimental cancers. However, their role in combination with radiotherapy in non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the radiosensitizing effect of GHRH antagonists in NSCLC. A549 and H522 NSCLC cell lines were exposed to ionizing radiation (IR) and GHRH antagonists MIA-602 and MIA-690, either individually or in combination. Cell viability and proliferation were evaluated by MTT, BrdU, flow cytofluorimetry, and clonogenic assays; gene and protein expression, signaling pathways, and apoptosis were analyzed by real-time PCR, Western blot, annexin staining, and caspase-3 assay. GHRH antagonists showed antitumor effects alone and potentiated IR-induced inhibition of cell viability and proliferation. The combination of MIA-690 and IR decreased the expression of GHRH receptor, its oncogenic splice variant 1, and IGF1 mRNA levels. Additionally, cell cycle inhibitors and proapoptotic markers were upregulated, whereas cyclins, oncogenic MYC, and the antiapoptotic protein Bcl-2 were downregulated. Radioresistance was prevented by MIA-690, which also blunted epithelial–mesenchymal transition by enhancing E-cadherin and reducing mesenchymal, oxidative, and proangiogenic effectors. Finally, both MIA-602 and MIA-690 enhanced radiosensitivity in primary human NSCLC cells. These findings highlight the potential of GHRH antagonists as radiosensitizers in NSCLC treatment. Full article

The prolyl-hydroxylase inhibitor (PHI), used effectively in several countries for the treatment of renal anemia, activates the multifunctional hypoxia-inducible factors (HIFs). While hypoxic conditions in tumors are known to affect the response to radiation therapy, the effect of PHI on the radiation response of cancer cells has not been determined. Hypoxic pretreatment increased the radiation sensitivity of A549 lung adenocarcinoma cells, whereas hypoxic culture after irradiation decreased the radiation sensitivity of HSC2 oral squamous cell carcinoma cells. Treatment of PC9 lung adenocarcinoma and HSC2 cells with the PHI FG-4592 significantly increased radiation resistance, whereas A549 and TIG3 lung fibroblast cells tended to be sensitized, suggesting cell type-specific differential effects of PHI. Quantitative RT-PCR analyses revealed that the basal and radiation-inducible expressions of DEC2, BAX, and BCL2 may be related to PHI-mediated radiation responses. Knock-down experiments showed that silencing of DEC2 sensitized both A549 and PC9 cells under PHI-treated conditions. On the other hand, silencing of p53, which regulates BAX/BCL2, desensitized A549 cells expressing wild-type p53, but not PC9 cells, with mutant-type p53, to irradiation, regardless of whether PHI was treated or not. Taken together, PHI modifies radiation responses in a cell type-specific manner, possibly through DEC2 signaling. Full article

Cartilage oligomeric matrix protein (COMP) is an extracellular matrix protein that has recently been associated with worse patient outcomes in breast, prostate, colorectal and hepatocellular cancers. This study aimed to determine whether COMP was also associated with increased progression and resistance to radiation in non-small cell lung cancer (NSCLC). The proliferation, migration, invasion and cell viability of wild-type and COMP overexpressing NSCLC cell lines were assessed when treated with exogenous COMP, with or without radiation. In addition, these cells were treated with inhibitors of downstream signaling intermediates of COMP. Proteomics were performed on the A549 cell line treated with COMP, radiation and inhibitors. NSCLC cells treated with COMP or overexpressing COMP had greater proliferation, migration, invasion and viability when irradiated compared to non-overexpressed cells treated with radiation alone, but this effect was reversed when treated with Src or PI3k inhibitors. The NCI-H1437 cell line exhibited a decrease in proliferation when treated with exogenous COMP, however COMP overexpression mitigated the radiation-induced reduction. Proteomics analyses indicate that COMP promotes oxidative phosphorylation and drug resistance pathways. Therefore, COMP overexpression and treatment with exogenous COMP appears to protect NSCLC cells against radiation in vitro, however treatment with inhibitors reverses COMP-mediated protection and progression. Full article

Breast cancer therapies have dramatically improved survival rates, but their long-term effects, especially on aging survivors, need careful consideration. This review delves into how breast cancer treatments and aging intersect, focusing on the epigenetic changes triggered by chemotherapy, radiation, hormonal treatments, and targeted therapies. Treatments can speed up biological aging by altering DNA methylation, histone modifications, and chromatin remodeling, affecting gene expression without changing the DNA sequence itself. The review explains the double-edged sword effect of therapy-induced epigenetic modifications, which help fight cancer but also accelerate aging. Chemotherapy and targeted therapies, in particular, impact DNA methylation and histone modifications, promoting chronic inflammation and shortening telomeres. These changes increase biological age, as seen in epigenetic clocks and biomarkers like p21, which also play roles in drug resistance and therapeutic decisions. Chronic inflammation, driven by higher levels of inflammatory cytokines such as TNF-α and IL-6 as well as telomere shortening, significantly contributes to the aging characteristics of breast cancer survivors. Non-coding RNAs, including microRNAs and long non-coding RNAs, are crucial in regulating gene expression and aging pathways altered by these treatments. This review explores new therapies targeting these epigenetic changes, like DNA methylation inhibitors, histone deacetylase inhibitors, and microRNA-based treatments, to reduce the aging effects of cancer therapy. Non-drug approaches, such as dietary changes and lifestyle modifications, also show promise in combating therapy-induced aging. It also highlights the clinical signs of aging-related side effects, such as heart and lung problems, endocrine and reproductive issues, and reduced quality of life. The development of comprehensive methods like the CHEMO-RADIAT score to predict major cardiovascular events after therapy is discussed. Understanding the epigenetic changes caused by breast cancer therapies offers valuable insights for creating interventions to enhance the health span and quality of life for survivors. Continued research is crucial to fully understand these epigenetic alterations and their long-term health impacts. Full article

Increased stemness of cancer cells exacerbates radioresistance, thereby greatly limiting the efficacy of radiotherapy. In order to study the changes in cancer cell stemness during radiotherapy, we established a radioresistance model of human non-small cell lung cancer A549 cells and obtained A549 radioresistant cells (A549-RR). We sampled the cells at different time points during the modeling process and investigated the heterogeneity of each group of cells using single-cell sequencing. Cells in the early stages of fractionated irradiation were found to be significantly up-regulated in stemness, and a subpopulation of cells producing this response was screened and referred to as “radiation-induced stemness-responsive cancer cells”. They were undergoing stemness response, energy metabolism reprogramming, and progressively differentiating into cells with more diverse and malignant phenotypes in order to attenuate the killing effect of radiation. Furthermore, we demonstrated that such responses might be driven by the activation of the EGFR-Hippo signaling pathway axis, which also plays a crucial role in the development of radioresistance. Our study reveals the dynamic evolution of cell subpopulation in cancer cells during fractionated radiotherapy; the early stage of irradiation can determine the destiny of the radiation-induced stemness-responsive cancer cells. The activation of stemness-like phenotypes during the development of radioresistance is not the result of dose accumulation but occurs during the early stage of radiotherapy with relatively low-dose irradiation. The degree of the radiation-induced stemness response of cancer cells mediated by the EGFR-Hippo signaling pathway might be a potential predictor of the efficacy of radiotherapy and the development of radioresistance. Full article

Background/Objectives: Stereotactic body radiation therapy (SBRT) has demonstrated high local control rates for inoperable early-stage lung cancers. However, 5–15% of patients experience local relapse within the irradiated volume after treatment, with limited curative salvage options. The aim of this review is to clarify the modalities and outcomes after a second course of SBRT in patients with local relapse after a previous lung SBRT. Methods: An exhaustive literature review was conducted to identify, analyse and summarise the results of 21 main studies. Results: Local repeat lung SBRT after a first course of SBRT showed a favourable local control at 1 and 2 years, ranging from 70 to 90% and 45 to 80%, respectively. Good overall survival rates were also observed at 1 and 2 years reaching up to 95% and 85%, respectively. Toxicity was rare but could be severe, with cases of Grade 4 and 5 toxicities (≈5%). An important dose relationship was observed between re-irradiation dose levels and local control, highlighting the importance of precise dosing. The cumulative doses impacting organs at risk were similarly associated with increased radiation-induced toxicity. Central lung lesions presented a higher risk for severe side effects compared to peripheral ones. Conclusions: In conclusion, repeat lung SBRT after a first course of SBRT represents a feasible treatment option in cases of local recurrence. In order to limit severe toxicity, patients must be carefully selected, and particular attention should be given to cumulative doses to organs at risk, as well as tumour location. Thus, further investigations are still needed to refine the optimal parameters for SBRT lung re-irradiation. Full article

More than 70% of cancer patients receive radiotherapy during their treatment, with consequent various side effects on normal cells due to high ionizing radiation doses despite tumor shrinkage. To date, many radioprotectors and radiosensitizers have been investigated in preclinical studies, but their use has been hampered by the high toxicity to normal cells or poor tumor radiosensitization effects. Genistein is a naturally occurring isoflavone found in soy products. It selectively sensitizes tumor cells to radiation while protecting normal cells from radiation-induced damage, thus improving the efficacy of radiotherapy and consequent therapeutic outcomes while reducing adverse effects. Genistein protects normal cells by its potent antioxidant effect that reduces oxidative stress and mitigates radiation-induced apoptosis and inflammation. Conversely, genistein increases the radiosensitivity of tumor cells through specific mechanisms such as the inhibition of DNA repair, the arrest of the cell cycle in the G₂/M phase, the generation of reactive oxygen species (ROS), and the modulation of apoptosis. These effects increase the cytotoxicity of radiation. Preclinical studies demonstrated genistein efficacy in various cancer models, such as breast, prostate, and lung cancer. Despite limited clinical studies, the existing evidence supports the potential of genistein in improving the therapeutic effect of radiotherapy. Future research should focus on dosage optimization and administration, the exploration of combination therapies, and long-term clinical trials to establish genistein benefits in clinical settings. Hence, the unique ability of genistein to improve the radiosensitivity of tumor cells while protecting normal cells could be a promising strategy to improve the efficacy and safety of radiotherapy. Full article

Background: Combining radiotherapy with targeted therapy benefits patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer (EGFRm NSCLC). However, the optimal strategy to combine EGFR tyrosine kinase inhibitors (TKIs) with radiotherapy for maximum efficacy and minimal toxicity is still uncertain. Notably, EVs, which serve as communication mediators among tumor cells, play a crucial role in the anti-tumor immune response. Methods To exploit the role of EVs in the delivery of tumor antigens, we formulated a therapeutic strategy that involves the use of radiation-induced tumor-derived EVs (TEXs) loaded onto dendritic cells (DCs) as a kind of vaccine in conjunction with EGFR TKIs and assessed the efficacy and safety of this approach in the treatment of EGFRm NSCLC. Results In our study, we characterized the release of immunogens as influenced by various modes of cell death, examining the impact of different levels of cell death under diverse irradiation modalities. Our results demonstrated that a radiation mode of 6Gy*3f exhibited the most promising potential to stimulate anti-tumor immune responses. This radiotherapy fraction, combined with TKIs, showed promising results in a tumor-bearing mouse model with an EGFR mutation, although there is a risk of radiation-associated pneumonitis. Furthermore, we found that 6Gy*3f-TEXs in vitro activate DCs and promote T cell proliferation as well as cytotoxic T lymphocyte-mediated tumor cell destruction. The administration of EGFR-TKIs combined DCs loaded with 6Gy*3f-TEXs exhibited the potential to inhibit tumor growth and mitigate the risk of pneumonitis. Together, the research shows that TEXs from high-dose fractionation radiation can mature DCs and boost the killing of cytotoxic T lymphocytes. Combining these DC vaccines with Osimertinib offers a promising and safe treatment for EGFRm NSCLC. Full article