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Journal of Cancer Research and... Sep 2009The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolytic ATP production, is the most widely investigated metabolic inhibitor for... (Review)
Review
The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolytic ATP production, is the most widely investigated metabolic inhibitor for targeting glucose metabolism. Besides depleting energy in cells, 2-DG has also been found to alter N-linked glycosylation leading to unfolded protein responses and induce changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, calcium influx, and apoptosis. Inhibition of cell proliferation and induction of apoptosis have been observed as cytotoxic effects in a wide variety of tumor cells in vitro, while sensitization of tumor cells to ionizing radiation and certain chemotherapeutic drugs is associated with enhanced mitotic as well as apoptotic cell death induced by the primary therapeutic agent. Therefore, there has been a considerable amount of interest in developing 2-DG as a therapeutic agent or adjuvant in the radiotherapy and chemotherapy of tumors.
Topics: Animals; Antineoplastic Agents; Deoxyglucose; Humans; In Vitro Techniques; Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Radiotherapy
PubMed: 20009290
DOI: 10.4103/0973-1482.55137 -
Biomolecules Jul 2016First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive... (Review)
Review
First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved, clinical problem. Unfortunately, the therapeutic refractoriness of solid tumors is the rule not the exception, and the ubiquity of resistance also extends to standard chemotherapy, molecularly targeted therapy and immunotherapy. Based on extrapolation from recent clinical inroads with epigenetic agents to prime refractory tumors for maximum sensitivity to concurrent or subsequent therapies, the radioresistant phenotype is potentially reversible, since aberrant epigenetic mechanisms are critical contributors to the evolution of resistant subpopulations of malignant cells. Within the framework of a syllogism, this review explores the emerging link between epigenetics and the development of radioresistance and makes the case that a strategy of pre- or co-treatment with epigenetic agents has the potential to, not only derepress inappropriately silenced genes, but also increase reactive oxygen species production, resulting in the restoration of radiosensitivity.
Topics: Epigenesis, Genetic; Humans; Neoplasms; Radiation Tolerance
PubMed: 27384589
DOI: 10.3390/biom6030032 -
Oncotarget Feb 2016Radiotherapy represents an important therapeutic strategy in the treatment of cancer cells. However, it often fails to eliminate all tumor cells because of the intrinsic... (Review)
Review
Radiotherapy represents an important therapeutic strategy in the treatment of cancer cells. However, it often fails to eliminate all tumor cells because of the intrinsic or acquired treatment resistance, which is the most common cause of tumor recurrence. Emerging evidences suggest that the Notch signaling pathway is an important pathway mediating radiation resistance in tumor cells. Successful targeting of Notch signaling requires a thorough understanding of Notch regulation and the context-dependent interactions between Notch and other therapeutically relevant pathways. Understanding these interactions will increase our ability to design rational combination regimens that are more likely to be safe and effective. Here we summarize the role of Notch in mediating resistance to radiotherapy, the different strategies to block Notch in cancer cells and how treatment scheduling can improve tumor response. Finally, we discuss a need for reliable Notch related biomarkers in specific tumors to measure pathway activity and to allow identification of a subset of patients who are likely to benefit from Notch targeted therapies.
Topics: Animals; Humans; Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Receptors, Notch
PubMed: 26713603
DOI: 10.18632/oncotarget.6714 -
International Journal of Molecular... May 2022The radiosensitization of tumor cells is one of the promising approaches for enhancing radiation damage to cancer cells and limiting radiation effects on normal tissue....
The radiosensitization of tumor cells is one of the promising approaches for enhancing radiation damage to cancer cells and limiting radiation effects on normal tissue. In this study, we performed a comprehensive screening of radiosensitization targets in human lung cancer cell line A549 using an shRNA library and identified () as a candidate target. is an innate restriction factor that inhibits HIV-1 infection as a cytidine deaminase. knockdown with siRNA showed an increased radiosensitivity in several cancer cell lines, including pancreatic cancer MIAPaCa2 cells and lung cancer A549 cells. Cell cycle analysis revealed that knockdown increased S-phase arrest in MIAPaCa2 and G2/M arrest in A549 cells after γ-irradiation. DNA double-strand break marker γH2AX level was increased in -knocked-down MIAPaCa2 cells after γ-irradiation. Using a xenograft model of A549 in mice, enhanced radiosensitivity by a combination of X-ray irradiation and knockdown was observed. These results suggest that the functional inhibition of sensitizes cancer cells to radiation by attenuating the activation of the DNA repair pathway, suggesting that could be useful as a target for the radiosensitization of cancer therapy.
Topics: APOBEC-3G Deaminase; Animals; Apoptosis; Cell Line, Tumor; Cytidine Deaminase; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Humans; Lung Neoplasms; Mice; Radiation Tolerance
PubMed: 35563460
DOI: 10.3390/ijms23095069 -
PloS One 2016Tardigrades belong to the most radiation tolerant animals on Earth, as documented by a number of studies using both low-LET and high-LET ionizing radiation. Previous...
Tardigrades belong to the most radiation tolerant animals on Earth, as documented by a number of studies using both low-LET and high-LET ionizing radiation. Previous studies have focused on semi-terrestrial species, which are also very tolerant to desiccation. The predominant view on the reason for the high radiation tolerance among these semi-terrestrial species is that it relies on molecular mechanisms that evolved as adaptations for surviving dehydration. In this study we report the first study on radiation tolerance in a marine tardigrade, Echiniscoides sigismundi. Adult specimens in the hydrated active state were exposed to doses of gamma radiation from 100 to 5000 Gy. The results showed little effect of radiation at 100 and 500 Gy but a clear decline in activity at 1000 Gy and higher. The highest dose survived was 4000 Gy, at which ca. 8% of the tardigrades were active 7 days after irradiation. LD50 in the first 7 days after irradiation was in the range of 1100-1600 Gy. Compared to previous studies on radiation tolerance in semi-terrestrial and limnic tardigrades, Echiniscoides sigismundi seems to have a lower tolerance. However, the species still fits into the category of tardigrades that have high tolerance to both desiccation and radiation, supporting the hypothesis that radiation tolerance is a by-product of adaptive mechanisms to survive desiccation. More studies on radiation tolerance in tardigrade species adapted to permanently wet conditions, both marine and freshwater, are needed to obtain a more comprehensive picture of the patterns of radiation tolerance.
Topics: Adaptation, Physiological; Animals; Aquatic Organisms; Gamma Rays; Radiation Tolerance; Tardigrada
PubMed: 27997621
DOI: 10.1371/journal.pone.0168884 -
Current Oncology (Toronto, Ont.) Feb 2022Even though it is only the 6th most common malignancy at the modal level, head and neck cancers are distinguished by a considerable treatment failure rate, especially by... (Review)
Review
Even though it is only the 6th most common malignancy at the modal level, head and neck cancers are distinguished by a considerable treatment failure rate, especially by locoregional recurrences, the intrinsic tumor radioresistance being one of the causes of this phenomenon. The efforts of radiobiological research of these cancers are oriented towards the identification of biomarkers associated with radioresistance and radiosensitivity in order to modulate the treatment so that the therapeutic benefit is maximum. Micro-RNAs (miRNAs, miRs), small single-stranded non-coding RNA molecules are currently being extensively evaluated as potential biomarkers in numerous diseases, including cancer. The evaluation of the potential of miRNAs to modulate or predict radiosensitivity or radioresistance, to anticipate the risk of recurrence and metastasis, and to differentiate different tumor subtypes is based on multiple mechanisms by which mRNAs control proliferation and apoptosis and interact with cell cycle phases or act as oncogenes with the potential to influence invasion promotion or tumor suppression. A refinement of radiosensitivity based on miRNAs with clinical and radiobiological application in head and neck cancers can lead to a personalization of radiotherapy. Thus, a miRNA signature can anticipate the risk of toxicity associated with chemoradiation, the possibility of obtaining locoregional control after treatment, and the recurrence and distant metastasis risk. The potential of miRNAs as an intrinsic predictor of sensitivity to chemotherapy may also guide the therapeutic decision toward choosing an escalation or de-escalation of concurrent or sequential systemic treatment. The choice of the irradiated dose, the fractional dose, the fractionation scheme, and the refining of the dose-volume constraints depending on the radiosensitivity of each tissue type estimated on a case-by-case basis by miRNAs profile are possible concepts for the future radiotherapy and radiobiology of head and neck cancers.
Topics: Head and Neck Neoplasms; Humans; MicroRNAs; Neoplasm Recurrence, Local; Radiation Tolerance; Radiobiology
PubMed: 35200568
DOI: 10.3390/curroncol29020069 -
Oncology (Williston Park, N.Y.) Jul 2017The understanding of the relationship between genetic variation and an individual patient's response to radiation therapy (RT) has gained significant ground over the... (Review)
Review
The understanding of the relationship between genetic variation and an individual patient's response to radiation therapy (RT) has gained significant ground over the past several years. Genetic markers have been identified that could ultimately serve as the foundation for predictive models in clinical practice, and that hold the potential to revolutionize the delivery of precision medicine in oncology. Single nucleotide polymorphisms, single genes, and/or gene signatures could ultimately serve as the basis for patient stratification in prospective clinical trials. Currently, molecular markers relevant to breast, lung, and head and neck cancers have been integrated into clinical practice and serve as predictive tools to guide systemic therapy. In the future, the use of predictive models based on genomic determinants may become standard practice in radiation oncology, offering the potential to further personalize the delivery of RT and optimize the therapeutic ratio.
Topics: Genetic Techniques; Humans; Neoplasms; Predictive Value of Tests; Prognosis; Radiation Tolerance; Radiotherapy; Treatment Outcome
PubMed: 28712100
DOI: No ID Found -
International Journal of Molecular... Feb 2018Radiotherapy is a well-established regimen for nearly half the cancer patients worldwide. However, not all cancer patients respond to irradiation treatment, and... (Review)
Review
Radiotherapy is a well-established regimen for nearly half the cancer patients worldwide. However, not all cancer patients respond to irradiation treatment, and radioresistance is highly associated with poor prognosis and risk of recurrence. Elucidation of the biological characteristics of radioresistance and development of effective prognostic markers to guide clinical decision making clearly remain an urgent medical requirement. In tumorigenic and radioresistant cancer cell populations, phenotypic switch is observed during the course of irradiation treatment, which is associated with both stable genetic and epigenetic changes. While the importance of epigenetic changes is widely accepted, the irradiation-triggered specific epigenetic alterations at the molecular level are incompletely defined. The present review provides a summary of current studies on the molecular functions of DNA and RNA m⁶A methylation, the key epigenetic mechanisms involved in regulating the expression of genetic information, in resistance to irradiation and cancer progression. We additionally discuss the effects of DNA methylation and RNA ⁶-methyladenosine (m⁶A) of specific genes in cancer progression, recurrence, and radioresistance. As epigenetic alterations could be reversed by drug treatment or inhibition of specific genes, they are also considered potential targets for anticancer therapy and/or radiotherapy sensitizers. The mechanisms of irradiation-induced alterations in DNA and RNA m⁶A methylation, and ways in which this understanding can be applied clinically, including utilization of methylation patterns as prognostic markers for cancer radiotherapy and their manipulation for anticancer therapy or use as radiotherapy sensitizers, have been further discussed.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; RNA Processing, Post-Transcriptional; Radiation Tolerance
PubMed: 29439529
DOI: 10.3390/ijms19020555 -
Experimental & Molecular Medicine Jun 2011Radiotherapy, frequently used for treatment of solid tumors, carries two main obstacles including acquired radioresistance in cancer cells during radiotherapy and normal... (Review)
Review
Radiotherapy, frequently used for treatment of solid tumors, carries two main obstacles including acquired radioresistance in cancer cells during radiotherapy and normal tissue injury. Phenylpropanoids, which are naturally occurring phytochemicals found in plants, have been identified as potential radiotherapeutic agents due to their anti-cancer activity and relatively safe levels of cytotoxicity. Various studies have proposed that these compounds could not only sensitize cancer cells to radiation resulting in inhibition of growth and cell death but also protect normal cells against radiation-induced damage. This review is intended to provide an overview of recent investigations on the usage of phenylpropanoids in combination with radiotherapy in cancer treatment.
Topics: Antineoplastic Agents; Apoptosis; Chromones; Combined Modality Therapy; Cytoprotection; Humans; Neoplasms; Phenylpropionates; Plants; Radiation Tolerance; Radiation-Sensitizing Agents; Radiotherapy
PubMed: 21483230
DOI: 10.3858/emm.2011.43.6.034 -
Current Molecular Pharmacology 2018Each year, millions of people die from cancer. Radiotherapy is one of the main treatment strategies for cancer patients. Despite the beneficial roles of treatment with... (Review)
Review
BACKGROUND
Each year, millions of people die from cancer. Radiotherapy is one of the main treatment strategies for cancer patients. Despite the beneficial roles of treatment with radiation, several side effects may threaten normal tissues of patients in the years after treatment.
DISCUSSION
Moreover, high incidences of second primary cancers may reduce therapeutic ratio of radiotherapy. The search for appropriate targets of radiosensitization of tumor cells as well as radioprotection of normal tissues is one of the most interesting aims in radiobiology. Cyclooxygenase-2 (COX-2), as an inflammatory mediator has attracted interests for both aims. COX-2 activity is associated with ROS production and inflammatory signs in normal tissues. These effects further amplify radiation toxicity in irradiated cells as well as adjacent cells through a phenomenon known as Bystander effect. Increased COX-2 expression in distant non-irradiated tissues causes oxidative DNA damage and elevated cancer risk. Moreover, in tumors, the activation of this enzyme can increase resistance of malignant cells to radiotherapy. Hence, the inhibition of COX-2 has been proposed for better therapeutic response and amelioration of normal tissues. Celecoxib is one of the most studied COX-2 inhibitor for radiosensitization and radioprotection, while some other inhibitors have shown interesting results.
CONCLUSION
In this review, we describe the role of COX-2 in radiation normal tissue injury as well as irradiated bystander and non-targeted cells. In addition, mechanisms of COX-2 induced tumor resistance to radiotherapy and the potential role of COX-2 inhibition are discussed.
Topics: Bystander Effect; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Drug Resistance, Neoplasm; Humans; Radiation Tolerance; Radiotherapy
PubMed: 29468988
DOI: 10.2174/1874467211666180219102520