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Cancer Gene Therapy Mar 2015Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided... (Review)
Review
Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy.
Topics: Animals; Gene Expression; Genetic Therapy; Humans; Neoplasms; Radiation Injuries; Radiation Tolerance; Transgenes
PubMed: 25721205
DOI: 10.1038/cgt.2015.8 -
International Journal of Radiation... 2022The aim of this work is to review the published studies on radiation resistance mechanisms and molecular markers involved in different tumors. The revision has been... (Review)
Review
PURPOSE
The aim of this work is to review the published studies on radiation resistance mechanisms and molecular markers involved in different tumors. The revision has been focused in the last 5 years (2016-2021).
CONCLUSIONS
Radioresistance is a cause of concern as it causes failure of radiation therapy and subsequent tumor relapse. Combination chemotherapy and radiation therapy are clinically successful in treating many types of tumors. Despite continued improvements in cancer treatment, locoregional recurrence or metastatic spread continues to occur in a high proportion of patients after being treated with radiation therapy or combination treatments. There is strong evidence that cancer stem cells contribute to radiation resistance, contributing to treatment failure. The mechanisms of radiation resistance in different tumors are not fully understood. A better understanding of cancer stem cells and the associated signaling pathways that regulate radiation resistance will open up new strategies for treating cancer by radiation therapy. Radiation can damage malignant cells mainly by the induction of DNA double-strand breaks. However, in some tumors appear resistant cells that repopulate the tumor following therapy leading over time to the failure of the treatment. Native mechanisms and induced pathways are the cause of radiation resistance. It has been described that numerous molecular markers acting through numerous mechanisms of action involved in radiation resistance, such as apoptosis resistance, alterations of cell growth, proliferation and DNA repair, hypoxia, increase in invasiveness and migration capacity, cell cycle alterations, and expression of heat shock proteins, among others. Therefore, resistance to radiation is a multifactorial phenomenon that, in different cell types, occurs through different regulatory mechanisms in which different molecules intervene. Resistance can be acquired by altering different regulatory pathways in different tumors. The knowledge of radiation resistance markers could help in the classification and treatment of patients with more aggressive tumors.
Topics: Cell Cycle; DNA Breaks, Double-Stranded; DNA Repair; Humans; Neoplasms; Radiation Tolerance
PubMed: 35225732
DOI: 10.1080/09553002.2022.2047825 -
Current Opinion in Oncology Mar 2022Radiotherapy has been proven to be useful but insufficient in melanoma management due to the intrinsic radioresistance of melanoma cells. Elucidation of the molecular... (Review)
Review
PURPOSE OF REVIEW
Radiotherapy has been proven to be useful but insufficient in melanoma management due to the intrinsic radioresistance of melanoma cells. Elucidation of the molecular mechanisms and pathways related to resistance/sensitivity to radiotherapy in melanoma is of paramount importance. In this review, we will summarize and discuss the recent 'discoveries' and advances in radiosensitivity determinants in melanoma.
RECENT FINDINGS
The different levels of radiosensitivity among the various melanoma tumors could be attributed to the DNA damage signaling and repair proteins, tumor microenvironment, hypoxia, cell metabolism, glutathione and redox balance, protein kinase signaling pathways as well as pigmentation and melanin content.
SUMMARY
It is therapeutically important to elucidate the factors involved in radiation resistance/sensitivity of melanoma. More importantly, improving radiosensitivity may 'widen the clinical utility' in melanoma of this important therapeutic modality.
Topics: DNA Damage; Humans; Melanoma; Radiation Tolerance; Tumor Microenvironment
PubMed: 35013044
DOI: 10.1097/CCO.0000000000000818 -
Radiation Research Jun 2016Resistance to radiation is considered to be an important reason for local failure after radiotherapy and tumor recurrence. However, the exact mechanisms of tumor... (Review)
Review
Resistance to radiation is considered to be an important reason for local failure after radiotherapy and tumor recurrence. However, the exact mechanisms of tumor resistance remain poorly understood. Current investigations of microRNAs as potential diagnostic and therapeutic tools for cancer treatment have shown promising results. With respect to radiotherapy resistance and response, there is now emerging evidence that microRNAs modulate key cellular pathways that mediate response to radiation. These data suggest that microRNAs might have significant potential as targets for the development of new therapeutic strategies to overcome radioresistance in cancer. This review summarizes the current literature pertinent to the influence of microRNAs in the response to radiotherapy for cancer treatment, with an emphasis on microRNAs as novel diagnostic and prognostic markers, as well as their potential to alter radiosensitivity.
Topics: Animals; Humans; MicroRNAs; Neoplasms; Radiation Tolerance; Treatment Outcome
PubMed: 27223830
DOI: 10.1667/RR14370.1 -
Clinical Cancer Research : An Official... Mar 2019The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in... (Review)
Review
The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in treating locally advanced diseases, thus requiring them to be combined with standard treatments in the hope of producing synergistic antitumor responses. Radiotherapy, in particular, has long been hypothesized to have actions complementary to those of immune checkpoint blockade, and a growing body of evidence indicates that cancer immunotherapy may also have radiosensitizing effects, which would provide unique benefit for locoregional treatments. Recent studies have demonstrated that when immune cells are activated by immunotherapeutics, they can reprogram the tumor microenvironment in ways that may potentially increase the radiosensitivity of the tumor. In this review, we highlight the evidence that supports reciprocal interactions between cancer immunotherapy and radiotherapy, where in addition to the traditional notion that radiation serves to enhance the activation of antitumor immunity, an alternative scenario also exists in which T-cell activation by cancer immunotherapy may sensitize tumors to radiation treatment through mechanisms that include normalization of the tumor vasculature and tissue hypoxia. We describe the empirical observations from preclinical models that support such effects and discuss their implications for future research and trial design.
Topics: Animals; Antineoplastic Agents, Immunological; Cell Line, Tumor; Clinical Trials as Topic; Combined Modality Therapy; Costimulatory and Inhibitory T-Cell Receptors; Disease Models, Animal; Humans; Immunotherapy; Neoplasms; Radiation Tolerance; Radiotherapy; Research Design; T-Lymphocytes; Tumor Escape; Tumor Microenvironment
PubMed: 30413527
DOI: 10.1158/1078-0432.CCR-18-2581 -
Annals of the ICRP Oct 2018In the past few decades, it has become increasingly evident that sensitivity to ionising radiation is variable. This is true for tissue reactions (deterministic effects)... (Review)
Review
In the past few decades, it has become increasingly evident that sensitivity to ionising radiation is variable. This is true for tissue reactions (deterministic effects) after high doses of radiation, for stochastic effects following moderate and possibly low doses, and conceivably also for non-cancer effects such as cardiovascular disease, the causal pathway(s) of which are not yet fully understood. A high sensitivity to deterministic effects is not necessarily correlated with a high sensitivity to stochastic effects. The concept of individual sensitivity to high and low doses of radiation has long been supported by data from patients with certain rare hereditary conditions. However, these syndromes only affect a small proportion of the general population. More relevant to the majority of the population is the notion that some part of the genetic contribution defining radiation sensitivity may follow a polygenic model, which predicts elevated risk resulting from the inheritance of many low-penetrance risk-modulating alleles. Can the different forms of individual radiation sensitivities be inferred from the reaction of cells exposed ex vivo to ionising radiation? Can they be inferred from analyses of individual genotypes? This paper reviews current evidence from studies of late adverse tissue reactions after radiotherapy in potentially sensitive groups, including data from functional assays, candidate gene approaches, and genome-wide association studies. It focuses on studies published in 2013 or later because a comprehensive review of earlier studies was published previously in a report by the UK Advisory Group on Ionising Radiation.
Topics: Dose-Response Relationship, Radiation; Humans; Radiation Protection; Radiation Tolerance; Radiation, Ionizing
PubMed: 29648458
DOI: 10.1177/0146645318764091 -
Frontiers in Endocrinology 2021Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over the last... (Review)
Review
Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over the last decade our understanding of the molecular foundation of thyroid function and carcinogenesis has driven the development of many novel therapeutics. These include FDA approved tyrosine kinase inhibitors and small molecular inhibitors of VEGFR, BRAF, MEK, NTRK and RET, which collectively have significantly changed the prognostic outlook for this patient population. Some therapeutics can re-sensitize de-differentiated cancers to iodine, allowing for radioactive iodine treatment and improved disease control. Remarkably, there is now an FDA approved treatment for BRAF-mutated patients with anaplastic thyroid cancer, previously considered invariably and rapidly fatal. The treatment landscape for iodine-resistant thyroid cancer is changing rapidly with many new targets, therapeutics, clinical trials, and approved treatments. We provide an up-to-date review of novel therapeutic options in the treatment of iodine-resistant thyroid cancer.
Topics: Humans; Iodine Radioisotopes; Radiation Tolerance; Therapies, Investigational; Thyroid Neoplasms; Treatment Failure
PubMed: 34335481
DOI: 10.3389/fendo.2021.720723 -
Biochimica Et Biophysica Acta. Reviews... Aug 2017Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of... (Review)
Review
Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of intrinsic and acquired radioresistance. Identification of molecular mechanisms that compromise the efficacy of radiation therapy and targeting these pathways is paramount for improving radiation response in PC patients. In this review, we have summarized molecular mechanisms associated with the radio-resistant phenotype of PC. Briefly, we discuss the reversible and irreversible biological consequences of radiotherapy, such as DNA damage and DNA repair, mechanisms of cancer cell survival and radiation-induced apoptosis following radiotherapy. We further describe various small molecule inhibitors and molecular targeting agents currently being tested in preclinical and clinical studies as potential radiosensitizers for PC. Notably, we draw attention towards the confounding effects of cancer stem cells, immune system, and the tumor microenvironment in the context of PC radioresistance and radiosensitization. Finally, we discuss the need for examining selective radioprotectors in light of the emerging evidence on radiation toxicity to non-target tissue associated with PC radiotherapy.
Topics: Animals; Apoptosis; DNA Damage; DNA Repair; Humans; Pancreatic Neoplasms; Radiation Tolerance; Tumor Microenvironment
PubMed: 28249796
DOI: 10.1016/j.bbcan.2017.02.003 -
Bioscience Reports Oct 2023Radiotherapy is utilised in the treatment of ∼50% of all human cancers, which predominantly employs photon radiation. However, particle radiotherapy elicits... (Review)
Review
Radiotherapy is utilised in the treatment of ∼50% of all human cancers, which predominantly employs photon radiation. However, particle radiotherapy elicits significant benefits over conventional photons due to more precise dose deposition and increased linear energy transfer (LET) that generates an enhanced therapeutic response. Specifically, proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) are characterised by a Bragg peak, which generates a low entrance radiation dose, with the majority of the energy deposition being defined within a small region which can be specifically targeted to the tumour, followed by a low exit dose. PBT is deemed relatively low-LET whereas CIRT is more densely ionising and therefore high LET. Despite the radiotherapy type, tumour cell killing relies heavily on the introduction of DNA damage that overwhelms the repair capacity of the tumour cells. It is known that DNA damage complexity increases with LET that leads to enhanced biological effectiveness, although the specific DNA repair pathways that are activated following the different radiation sources is unclear. This knowledge is required to determine whether specific proteins and enzymes within these pathways can be targeted to further increase the efficacy of the radiation. In this review, we provide an overview of the different radiation modalities and the DNA repair pathways that are responsive to these. We also provide up-to-date knowledge of studies examining the impact of LET and DNA damage complexity on DNA repair pathway choice, followed by evidence on how enzymes within these pathways could potentially be therapeutically exploited to further increase tumour radiosensitivity, and therefore radiotherapy efficacy.
Topics: Humans; DNA Damage; Radiation, Ionizing; Neoplasms; Photons; Radiation Tolerance
PubMed: 37695845
DOI: 10.1042/BSR20222586 -
Journal of Experimental & Clinical... Feb 2019S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates...
BACKGROUND
S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates their ubiquitination. Programmed cell death protein 4 (PDCD4) is a tumor suppressor gene that plays a role in cell apoptosis and DNA-damage response via interacting with eukaryotic initiation factor-4A (eIF4A) and P53. Previous research showed SKP2 may interact with PDCD4, however the relationship between SKP2 and PDCD4 is unclear.
METHODS
To validate the interaction between SKP2 and PDCD4, mass spectrometric analysis and reciprocal co-immunoprecipitation (Co-IP) experiments were performed. SKP2 stably overexpressed or knockdown breast cancer cell lines were established and western blot was used to detect proteins changes before and after radiation. In vitro and in vivo experiments were performed to verify whether SKP2 inhibits cell apoptosis and promotes DNA-damage response via PDCD4 suppression. SMIP004 was used to test the effect of radiotherapy combined with SKP2 inhibitor.
RESULTS
We found that SKP2 remarkably promoted PDCD4 phosphorylation, ubiquitination and degradation. SKP2 promoted cell proliferation, inhibited cell apoptosis and enhanced the response to DNA-damage via PDCD4 suppression in breast cancer. SKP2 and PDCD4 showed negative correlation in human breast cancer tissues. Radiotherapy combine with SKP2 inhibitor SMIP004 showed significant inhibitory effects on breast cancer cells in vitro and in vivo.
CONCLUSIONS
We identify PDCD4 as an important ubiquitination substrate of SKP2. SKP2 promotes breast cancer tumorigenesis and radiation tolerance via PDCD4 degradation. Radiotherapy combine with SKP2-targeted adjuvant therapy may improve breast cancer patient survival in clinical medicine.
Topics: Animals; Apoptosis Regulatory Proteins; Breast Neoplasms; Carcinogenesis; Female; Humans; Radiation Tolerance; S-Phase Kinase-Associated Proteins; Ubiquitination
PubMed: 30760284
DOI: 10.1186/s13046-019-1069-3