Improve Cancer Treatment Outcomes Research Articles

Vitamin Nutritional Status in Patients with Pancreatic Cancer: A Narrative Review.

Due to the high mortality rate in Western countries, pancreatic cancer is considered one of the big killers, leaving patients and their families with little hope upon diagnosis. Although surgical and drug therapies are critical for cancer patients to improve life expectancy and alleviation of suffering, nutrition plays a key role in improving cancer treatment outcomes. This narrative review, conducted as part of the activities of the Italian Society of Human Nutrition (SINU) working group in oncology, focuses on the prevalence of vitamin malnutrition among pancreatic cancer patients. The results of the literature search show that pancreatic cancer patients are at a heightened risk of water-soluble vitamin deficiencies, particularly of vitamins B1, B3, and B6. Additionally, they also face an increased risk of deficiency of fat-soluble vitamins. Among these vitamins, the potential role of vitamin D in pancreatic cancer has garnered the most attention, with its plasma levels being identified as a significant factor in patient survival. Investigating vitamin nutritional status could provide valuable insights for incorporating nutritional approaches into the prevention and treatment of pancreatic cancer, thereby reducing the exacerbation of symptoms associated with the diagnosis.

Drug repurposing for cancer therapy.

Cancer, a complex and multifactorial disease, presents a significant challenge to global health. Despite significant advances in surgical, radiotherapeutic and immunological approaches, which have improved cancer treatment outcomes, drug therapy continues to serve as a key therapeutic strategy. However, the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects, and thus there remains a critical need to develop novel cancer therapeutics. One promising strategy that has received widespread attention in recent years is drug repurposing: the identification of new applications for existing, clinically approved drugs. Drug repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective, proven to be safe, and can significantly expedite the drug development process due to their already established safety profiles. In light of this, the present review offers a comprehensive overview of the various methods employed in drug repurposing, specifically focusing on the repurposing of drugs to treat cancer. We describe the antitumor properties of candidate drugs, and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor microenvironment. In addition, we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug delivery. We also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy regimen. To conclude, we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.

Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma.

Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.

Applications of the partial-order continual reassessment method in the early development of treatment combinations.

Combination therapy is increasingly being explored as a promising approach for improving cancer treatment outcomes. However, identifying effective dose combinations in early oncology drug development is challenging due to limited sample sizes in early-phase clinical trials. This task becomes even more complex when multiple agents are being escalated simultaneously, potentially leading to a loss of monotonic toxicity order with respect to the dose. Traditional single-agent trial designs are insufficient for this multi-dimensional problem, necessitating the development and implementation of dose-finding methods specifically designed for drug combinations. While, in practice, approaches to this problem have focused on preselecting combinations with a known toxicity order and applying single-agent designs, this limits the number of combinations considered and may miss promising dose combinations. In recent years, several novel designs have been proposed for exploring partially ordered drug combination spaces with the goal of identifying a maximum tolerated dose combination, based on safety, or an optimal dose combination, based on toxicity and efficacy. However, their implementation in clinical practice remains limited. In this article, we describe the application of the partial order continual reassessment method and its extensions for combination therapies in early-phase clinical trials. We present completed trials that use safety endpoints to identify maximum tolerated dose combinations and adaptively use both safety and efficacy endpoints to determine optimal treatment strategies. We discuss the effectiveness of the partial-order continual reassessment method and its extensions in identifying optimal treatment strategies and provide our experience with executing these novel adaptive designs in practice. By utilizing innovative dose-finding methods, researchers and clinicians can more effectively navigate the challenges of combination therapy development, ultimately improving patient outcomes in the treatment of cancer.

Regulation of ferroptosis by PI3K/Akt signaling pathway: a promising therapeutic axis in cancer.

The global challenge posed by cancer, marked by rising incidence and mortality rates, underscores the urgency for innovative therapeutic approaches. The PI3K/Akt signaling pathway, frequently amplified in various cancers, is central in regulating essential cellular processes. Its dysregulation, often stemming from genetic mutations, significantly contributes to cancer initiation, progression, and resistance to therapy. Concurrently, ferroptosis, a recently discovered form of regulated cell death characterized by iron-dependent processes and lipid reactive oxygen species buildup, holds implications for diseases, including cancer. Exploring the interplay between the dysregulated PI3K/Akt pathway and ferroptosis unveils potential insights into the molecular mechanisms driving or inhibiting ferroptotic processes in cancer cells. Evidence suggests that inhibiting the PI3K/Akt pathway may sensitize cancer cells to ferroptosis induction, offering a promising strategy to overcome drug resistance. This review aims to provide a comprehensive exploration of this interplay, shedding light on the potential for disrupting the PI3K/Akt pathway to enhance ferroptosis as an alternative route for inducing cell death and improving cancer treatment outcomes.

Artificial Intelligence Application for Anti-tumor Drug Synergy Prediction

Abstract: Currently, the main therapeutic methods for cancer include surgery, radiation therapy, and chemotherapy. However, chemotherapy still plays an important role in tumor therapy. Due to the variety of pathogenic factors, the development process of tumors is complex and regulated by many factors, and the treatment of a single drug is easy to cause the human body to produce a drug-resistant phenotype to specific drugs and eventually leads to treatment failure. In the process of clinical tumor treatment, the combination of multiple drugs can produce stronger anti-tumor effects by regulating multiple mechanisms and can reduce the problem of tumor drug resistance while reducing the toxic side effects of drugs. Therefore, it is still a great challenge to construct an efficient and accurate screening method that can systematically consider the synergistic anti- tumor effects of multiple drugs. However, anti-tumor drug synergy prediction is of importance in improving cancer treatment outcomes. However, identifying effective drug combinations remains a complex and challenging task. This review provides a comprehensive overview of cancer drug synergy therapy and the application of artificial intelligence (AI) techniques in cancer drug synergy prediction. In addition, we discuss the challenges and perspectives associated with deep learning approaches. In conclusion, the review of the AI techniques' application in cancer drug synergy prediction can further advance our understanding of cancer drug synergy and provide more effective treatment plans and reasonable drug use strategies for clinical guidance.

A Novel Carrier Based on DNA and Exosome to Sustained Release of 5‐Fluorouracil Anticancer Drug

AbstractThe development of effective drug delivery systems is crucial for improving cancer treatment outcomes. A promising carrier using a combination of DNA and exosomes (EXO) was synthesized to sustain the release of the powerful anticancer drug 5‐fluorouracil (5‐FU). The carrier was prepared by encapsulating 5‐FU‐loaded exosomes (5‐FU.EXO) in the heated DNA carriers (5‐FU.EXO@DNA). Alteration of the DNA structure was studied using molecular dynamics. The physicochemical properties of the carriers were characterized using fourier‐transform infrared spectroscopy (FTIR), field‐emission scanning electron microscopy (FESEM), and dynamic light scattering (DLS). The 5‐FU.EXO@DNA carrier exhibited good stability and biocompatibility, with a uniform size distribution (709±269 nm) and a zeta potential of +312 mV. The interaction between 5‐FU and DNA was confirmed using molecular docking. In vitro release studies showed that both 5‐FU@DNA and 5‐FU.EXO@DNA carriers achieved sustained release of 5‐FU for 576 h, with cumulative releases of approximately 83 % and 89 %, respectively. The 5‐FU release profile showed 40 % release over 86 h. The release rate and other kinetic parameters were also determined. Furthermore, the release kinetics followed by the Korsmeyer‐Peppas model and the diffusion mechanism plays a significant role in controlling the release process.

MICROCAPSULES IN MEDICINE: REVIEW OF SCIENTIFIC LITERATURE AND PROSPECTS OF APPLICATION IN MICROENCAPSULATION OF ANTICANCER DRUGS

Microcapsules are an innovative form of drug delivery into the human body, which has attracted attention due to its great capabilities in various fields of healthcare. These small particles with a special shell have the potential to improve the processes of drug therapy, diagnosis, and treatment of dis-eases (for example, cancer), during which the effectiveness increases and the toxicity of many drugs decreases. Due to their small size (from 100 to 500 microns), microcapsules can transfer and protect the active components of drugs, ensuring their accurate and targeted delivery to the site of ac-tion in the body. Currently, a promising area is the study of microcapsules in which antitumor drugs are placed. The active substance is delivered di-rectly to cancer cells, which increases the concentration of the drug in the tumor and at the same time reduces its effect on healthy tissues. This ap-proach will help improve cancer treatment outcomes and increase the chances of a successful recovery for patients without any dangerous side ef-fects. The purpose of the work is to analyze modern research related to the microcapsulation of various drugs, especially in the field of oncology. The literature is analyzed, including scientific domestic and foreign publications that have been written over the past ten years. The analysis of existing studies related to the use of microcapsules in medicine is presented. Some methods of obtaining a new form, its types, and applications in medicine, in particular in oncology, are considered. This review provides valuable information on a variety of research methods and promising uses of a process such as microcapsulation for the delivery of anticancer drugs, and can be one of the important resources for researchers developing new therapeutic approaches, as well as for doctors applying advanced cancer treatments through innovative therapies

Dynamic interplay of nuclear receptors in tumor cell plasticity and drug resistance: Shifting gears in malignant transformations and applications in cancer therapeutics.

Recent advances have brought forth the complex interplay between tumor cell plasticity and its consequential impact on drug resistance and tumor recurrence, both of which are critical determinants of neoplastic progression and therapeutic efficacy. Various forms of tumor cell plasticity, instrumental in facilitating neoplastic cells to develop drug resistance, include epithelial-mesenchymal transition (EMT) alternatively termed epithelial-mesenchymal plasticity, the acquisition of cancer stem cell (CSC) attributes, and transdifferentiation into diverse cell lineages. Nuclear receptors (NRs) are a superfamily of transcription factors (TFs) that play an essential role in regulating a multitude of cellular processes, including cell proliferation,differentiation, and apoptosis. NRs have been implicated to play a critical role in modulating gene expression associated with tumor cell plasticity and drug resistance. This review aims to provide a comprehensive overview of the current understanding of how NRs regulate these key aspects of cancer biology. We discuss the diverse mechanisms through which NRs influence tumor cell plasticity, including EMT, stemness, and metastasis. Further, we explore the intricate relationship between NRs and drug resistance, highlighting the impact of NR signaling on chemotherapy, radiotherapy andtargeted therapies. We also discuss the emerging therapeutic strategies targeting NRs to overcome tumor cell plasticity and drug resistance. This review also provides valuable insights into the current clinical trials that involve agonists or antagonists of NRs modulating various aspects of tumor cell plasticity, thereby delineating the potential of NRs as therapeutic targets for improved cancer treatment outcomes.

Identification of biological markers in cancer disease using explainable artificial intelligence

AbstractThe research aims to improve the prediction of drug sensitivity on cancer cell lines using gene expression data and molecular fingerprints of drugs. The proposed study uses a deep learning model, BioMarkerX, trained on the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets utilizing Particle Swarm Optimization technique to select specific genes as features. The model achieves high prediction accuracy with a Root Mean Square Error (RMSE) of 0.40 ± 0.02 and R2 of 0.83 ± 0.03 on the CCLE dataset, and an RMSE of 0.36 ± 0.05 and R2 of 0.83 ± 0.03 on the GDSC dataset. The approach also used an explainable artificial intelligence model to discover biological markers linked to cancer development. This can provide insights into targeted therapies for improving cancer treatment outcomes. Overall, the study presents an effective approach for identifying important biological markers relevant to cancer disease, aiding in the development of more efficient anticancer medications.

Evolution of Radiotherapy- A Brief Review

Beginning with the discovery of X-rays by Wilhelm Conrad Röntgen in 1895 and the subsequent application of X-rays for cancer treatment in 1896, the narrative unfolds through the advancements in radiation therapy modalities. The discussion covers External Beam Radiotherapy (EBRT), including various techniques like 3D-CRT, IMRT, IGRT, stereotactic radiotherapy, and proton therapy. Emerging technologies such as Tomotherapy, Stereotactic Radiosurgery (SRS), Boron Neutron Capture Therapy (BNCT), Carbon Ion Therapy, and Brachytherapy are explored, offering tailored approaches for different cancer types. The article delves into the history and advancements of brachytherapy, highlighting its techniques like intracavitary, interstitial, and HDR surface mould brachytherapy. The continuous pursuit of precision, efficacy, and reduced side effects in cancer treatment is evident throughout the narrative. The article emphasizes the crucial role of radiation therapy, employing various ionizing radiation types, in targeting and eradicating cancer cells while minimizing harm to normal cells. The ongoing quest for advancements in technology and techniques reflects the commitment to improving cancer treatment outcomes. This article provides a comprehensive overview of radiation therapy's historical evolution and current state in cancer treatment Keywords: Radiotherapy, EBRT, Brachytherapy, IMRT, SRS, IGRT, Proton therapy

Pyroptotic cell death: an emerging therapeutic opportunity for radiotherapy.

Pyroptotic cell death, an inflammatory form of programmed cell death (PCD), is emerging as a potential therapeutic opportunity for radiotherapy (RT). RT is commonly used for cancer treatment, but its effectiveness can be limited by tumor resistance and adverse effects on healthy tissues. Pyroptosis, characterized by cell swelling, membrane rupture, and release of pro-inflammatory cytokines, has been shown to enhance the immune response against cancer cells. By inducing pyroptotic cell death in tumor cells, RT has the potential to enhance treatment outcomes by stimulating anti-tumor immune responses and improving the overall efficacy of RT. Furthermore, the release of danger signals from pyroptotic cells can promote the recruitment and activation of immune cells, leading to a systemic immune response that may target distant metastases. Although further research is needed to fully understand the mechanisms and optimize the use of pyroptotic cell death in RT, it holds promise as a novel therapeutic strategy for improving cancer treatment outcomes. This review aims to synthesize recent research on the regulatory mechanisms underlying radiation-induced pyroptosis and to elucidate the potential significance of this process in RT. The insights gained from this analysis may inform strategies to enhance the efficacy of RT for tumors.

Deep Drug Synergy Prediction Network Using Modified Triangular Mutation-Based Differential Evolution.

Drug combination therapy is crucial in cancer treatment, but accurately predicting drug synergy remains a challenge due to the complexity of drug combinations. Machine learning and deep learning models have shown promise in drug combination prediction, but they suffer from issues such as gradient vanishing, overfitting, and parameter tuning. To address these problems, the deep drug synergy prediction network, named as EDNet is proposed that leverages a modified triangular mutation-based differential evolution algorithm. This algorithm evolves the initial connection weights and architecture-related attributes of the deep bidirectional mixture density network, improving its performance and addressing the aforementioned issues. EDNet automatically extracts relevant features and provides conditional probability distributions of output attributes. The performance of EDNet is evaluated over two well-known drug synergy datasets, NCI-ALMANAC and deep-synergy. The results demonstrate that EDNet outperforms the competing models. EDNet facilitates efficient drug interactions, enhancing the overall effectiveness of drug combinations for improved cancer treatment outcomes.

Cancer-Associated Fibroblasts in Gastrointestinal Cancers: Unveiling Their Dynamic Roles in the Tumor Microenvironment.

Gastrointestinal cancers are highly aggressive malignancies with significant mortality rates. Recent research emphasizes the critical role of the tumor microenvironment (TME) in these cancers, which includes cancer-associated fibroblasts (CAFs), a key component of the TME that have diverse origins, including fibroblasts, mesenchymal stem cells, and endothelial cells. Several markers, such as α-SMA and FAP, have been identified to label CAFs, and some specific markers may serve as potential therapeutic targets. In this review article, we summarize the literature on the multifaceted role of CAFs in tumor progression, including their effects on angiogenesis, immune suppression, invasion, and metastasis. In addition, we highlight the use of single-cell transcriptomics to understand CAF heterogeneity and their interactions within the TME. Moreover, we discuss the dynamic interplay between CAFs and the immune system, which contributes to immunosuppression in the TME, and the potential for CAF-targeted therapies and combination approaches with immunotherapy to improve cancer treatment outcomes.

Dynamic ultrasound molecular-targeted imaging of senescence in evaluation of lapatinib resistance in HER2-positive breast cancer.

Prolonged treatment of HER2+ breast cancer with lapatinib (LAP) causes cellular senescence and acquired drug resistance, which often associating with poor prognosis for patients. We aim to explore the correlation between cellular senescence and LAP resistance in HER2+ breast cancer, screen for molecular marker of reversible senescence, and construct targeted nanobubbles for ultrasound molecular imaging to dynamically evaluate LAP resistance. In this study, we established a new cellular model of reversible cellular senescence using LAP and HER2+ breast cancer cells and found that reversible senescence contributed to LAP resistance in HER2+ breast cancer. Then, we identified ecto-5'-nucleotidase (NT5E) as a marker of reversible senescence in HER2+ breast cancer. Based on this, we constructed NT5E-targeted nanobubbles (NT5E-FITC-NBs) as a new molecular imaging modality which could both target reversible senescent cells and be used for ultrasound imaging. NT5E-FITC-NBs showed excellent physical and imaging characteristics. As an ultrasound contrast agent, NT5E-FITC-NBs could accurately identify reversible senescent cells both in vitro and in vivo. Our data demonstrate that cellular senescence-based ultrasound-targeted imaging can identify reversible senescence and evaluate LAP resistance effectively in HER2+ breast cancer cells, which has the potential to improve cancer treatment outcomes by altering therapeutic strategies ahead of aggressive recurrences.

Using spore-forming bacteria to treat cancer: recent advancements in clostridial-based therapies

The use of bacteria in cancer therapy has emerged as a promising approach, offering unique advantages for targeted treatment and immunotherapy. This review paper explores some recent advances in the application of bacteria, particularly Clostridium species, in cancer therapy. For instance, the Clostridial-Directed Enzyme Prodrug Therapy (CDEPT) utilises non-pathogenic strains of Clostridium as carriers for targeted delivery of anti-cancer drugs to solid tumour cells. This strategy aims to minimise systemic side effects associated with traditional chemotherapy. Additionally, Clostridium novyi and Clostridium sporogenes present oncolytic properties and have shown potential for tumour regression in preclinical models. The engineering of these bacteria to produce cytokines, such as interleukin-12 (IL-12) and interleukin-2 (IL-2), further enhances their therapeutic potential by activating the immune system to target cancer cells. Clinical trials in humans have demonstrated the feasibility and safety of C. novyi-based therapies, and early results indicate potential efficacy in tumour regression. Overall, this review provides valuable insights into the multifaceted roles of bacteria, particularly Clostridium species, in cancer therapy, emphasizing their potential as targeted therapeutics and immunomodulators for improved cancer treatment outcomes.

Targeting copper metabolism: a promising strategy for cancer treatment.

Copper is an essential micronutrient that plays a critical role in many physiological processes. However, excessive copper accumulation in cancer cells has been linked to tumor growth and metastasis. This review article explores the potential of targeting copper metabolism as a promising strategy for cancer treatment. Excessive copper accumulation in cancer cells has been associated with tumor growth and metastasis. By disrupting copper homeostasis in cancer cells and inducing cell death through copper-dependent mechanisms (cuproplasia and cuprotosis, respectively), therapies can be developed with improved efficacy and reduced side effects. The article discusses the role of copper in biological processes, such as angiogenesis, immune response, and redox homeostasis. Various approaches for targeting copper metabolism in cancer treatment are examined, including the use of copper-dependent enzymes, copper-based compounds, and cuprotosis-related genes or proteins. The review also explores strategies like copper chelation therapy and nanotechnology for targeted delivery of copper-targeting agents. By understanding the intricate network of cuprotosis and its interactions with the tumor microenvironment and immune system, new targets for therapy can be identified, leading to improved cancer treatment outcomes. Overall, this comprehensive review highlights the significant potential of targeting copper metabolism as a promising and effective approach in cancer treatment, while providing valuable insights into the current state of research in this field.

Management of odontogenic foci of infection (dental caries, periodontal disease and odontogenic infections) in the oral functional management of patients receiving cancer treatments: Guidelines based on a systematic review

AbstractIn cancer treatment, perioperative oral functional management is used as a part of supportive care. Its main objectives are as follows: (1) preventing and reducing adverse events, (2) maintaining or improving nutritional status, (3) improving cancer treatment outcomes, (4) maintaining or improving quality of life, (5) providing high quality medical care through comprehensive oral care, (6) controlling odontogenic foci of infection, and (7) maintaining or improving oral function. A literature search was conducted using the electronic databases of Medical Journal and PubMed. Electronic database searches were performed using various combinations of the following key words: cancer, surgery, treatment, chemotherapy, radiotherapy and dental disease, oral care, oral management, dental intervention, oral health, dental care, and dental management. The selection of literature for inclusion in the review was restricted to dental management of patients receiving cancer treatment. In the course of the literature review, hand searches were also added as needed. The guideline was developed by summarizing the results of the review. Based on a review of the literature on the management of dental foci of infection in the oral functional management of patients undergoing cancer treatment, a guideline was developed by summarizing the results of the review. This report is a secondary publication of our previous review report “J. Stomatol. Soc. 70(4): 279–289. Dec 2021.”

SMILESynergy: Anticancer drug synergy prediction based on Transformer pre-trained model

The synergistic effect of drug combinations can solve the problem of acquired resistance to single drug therapy and has great potential for the treatment of complex diseases such as cancer. In this study, to explore the impact of interactions between different drug molecules on the effect of anticancer drugs, we proposed a Transformer-based deep learning prediction model-SMILESynergy. First, the drug text data-simplified molecular input line entry system (SMILES) were used to represent the drug molecules, and drug molecule isomers were generated through SMILES Enumeration for data augmentation. Then, the attention mechanism in the Transformer was used to encode and decode the drug molecules after data augmentation, and finally, a multi-layer perceptron (MLP) was connected to obtain the synergy value of the drugs. Experimental results showed that our model had a mean squared error of 51.34 in regression analysis, an accuracy of 0.97 in classification analysis, and better predictive performance than the DeepSynergy and MulinputSynergy models. SMILESynergy offers improved predictive performance to assist researchers in rapidly screening optimal drug combinations to improve cancer treatment outcomes.

Radio-resistance of hypoxic tumors: exploring the effects of oxygen and X-ray radiation on non-small lung cancer cell lines

BackgroundSolid tumors are often riddled with hypoxic areas, which develops as a result of high proliferation. Cancer cells willingly adapt and thrive in hypoxia by activating complex changes which contributes to survival and enhanced resistance to treatments, such as photon radiation. Photon radiation primarily relies on oxygen for the production of reactive oxygen species to induce DNA damage. The present in-vitro study aimed at investigating the biochemical responses of hypoxic non-small cell lung cancer (NSCLC) cells, particularly the effects on the DNA damage repair systems contributing to more radioresistant phenotypes and their pro- and anti-oxidant potential, within the first 24 h post-IR.MethodsNSCLC cell lines (H460, A549, Calu-1) were irradiated using varying X-ray doses under normoxia (21% O2) and hypoxia (0.1% O2). The overall cell survival was assessed by clonogenic assays. The extent of irradiation (IR)-induced DNA damage was evaluated by analyzing γ-H2AX foci induction and the altered expression of repair genes involved in non-homologous end joining and homologous recombination pathways. Moreover, cell-altered responses were investigated, including the nuclear and cytosolic hydrogen peroxide (H2O2) production, as well as the associated anti-oxidant potential, in particular some components related to the glutathione system.ResultsAnalysis of clonogenic survival revealed an enhanced radioresistance of the hypoxic NSCLC cells associated with reduced DNA damage and a downregulation of DNA repair genes. Moreover, nuclear H2O2 levels were IR-induced in a dose-dependent manner only under normoxia, and directly correlated with the DNA double-strand breaks. However, the observed nuclear H2O2 reduction in hypoxia appeared to be unaffected by IR, thus highlighting a possible reason for the enhanced radioresistance of the hypoxic NSCLC cells. The cellular antioxidant capacity was upregulated by IR in both oxygen conditions most likely helping to counteract the radiation effect on the cytosolic H2O2.ConclusionsIn conclusion, our data provide insight into the adaptive behavior of radiation-resistant hypoxic NSCLC cells, in particular their DNA repair and oxidative stress responses, which could contribute to lower DNA damage and higher cell survival rates following X-ray exposure. These findings may therefore help to identify potential targets for improving cancer treatment outcomes.