Radiation-induced cell death mechanisms

Abstract

The main goal when treating malignancies with radiation therapy is to deprive tumor cells of their reproductive potential. One approach to achieve this is by inducing tumor cell apoptosis. Accumulating evidences suggest that induction of apoptosis alone is insufficient to account for the therapeutic effect of radiotherapy. It has become obvious in the last few years that inhibition of the proliferative capacity of malignant cells following irradiation, especially with solid tumors, can occur via alternative cell death modalities or permanent cell cycle arrests, i.e., senescence. In this review, apoptosis and mitotic catastrophe, the two major cell deaths induced by radiation, are described and dissected in terms of activating mechanisms. Furthermore, treatment-induced senescence and its relevance for the outcome of radiotherapy of cancer will be discussed. The importance of p53 for the induction and execution of these different types of cell deaths is highlighted. The efficiency of radiotherapy and radioimmunotherapy has much to gain by understanding the cell death mechanisms that are induced in tumor cells following irradiation. Strategies to use specific inhibitors that will manipulate key molecules in these pathways in combination with radiation might potentiate therapy and enhance tumor cell kill.

Vitamin E content in fish oil emulsion does not prevent lipoperoxidative effects on human colorectal tumors

“…A two-parameter fluorescence-activated cell sorting (FACS) analysis was performed after cell staining with 5 mL of annexin V conjugated with fluorescein isothiocyanate and 5 mL of propidium iodide (PI) using a FACSFitc flow cytometer (BD Biosciences). PI staining was also used to examine morphologic nuclear abnormalities by confocal laser scanning LSM510 microscopy (Carl Zeiss, Feldbach, Switzerland) according to a published protocol [18] (n ¼ 3/condition).…”

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…5,6 In this regard, tumor cells undergoing immunogenic forms of cell death are known to release damage-associated molecular patterns (DAMPs), including heat shock protein 70 (HSP70), high mobility group box1 (HMGB1), and ATP, thereby supporting the recruitment and maturation of APCs. 7–10 However, the mode of cell death induced by ionizing irradiation is not uniform, and it clearly depends on the irradiation dose, the fractionation regimen, and the genetic repertoire of the irradiated cells. 3,10 Proliferating cells of the hematopoietic system predominantly undergo apoptosis upon irradiation, as characterized by externalization of phosphatidylserine, membrane blebbing, chromatin condensation, and DNA fragmentation, while the integrity of the plasma membrane remains intact.…”

“…7–10 However, the mode of cell death induced by ionizing irradiation is not uniform, and it clearly depends on the irradiation dose, the fractionation regimen, and the genetic repertoire of the irradiated cells. 3,10 Proliferating cells of the hematopoietic system predominantly undergo apoptosis upon irradiation, as characterized by externalization of phosphatidylserine, membrane blebbing, chromatin condensation, and DNA fragmentation, while the integrity of the plasma membrane remains intact. 11 If apoptotic cells are not removed in time by professional or non-professional phagocytes, they progress into secondary, post-apoptotic necrosis: The integrity of the plasma membrane collapses, and intracellular contents, including DAMPs, are released.…”

“…More frequently however, programmed necroptosis or uncontrolled necrosis are observed, encompassing plasma membrane permeabilization and/or rupture, cellular disintegration, and leakage of the intracellular contents into the surroundings. 10,14 In parallel to the different modes of cell death, the induction of systemic immune responses by local radiotherapy – known as radiotherapy’s abscopal effects – varies widely with the model systems and the radiation regimen employed. 6,15–17 Investigations in different mouse tumor models revealed that radiotherapy-induced anti-tumor immune reactions, which are essentially dependent on type-I interferons (produced by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) axis), APCs, and cytotoxic CD8 + T cells, are exclusively stimulated by high single doses (10–20 Gy).…”

Radiotherapy and Immunotherapy Combinations in Non-small Cell Lung Cancer: A Promising Future?

“…The key focus in radiobiology over the last decades has been the mechanism of radiotherapy-induced tumour cell death and research on radiation induced damage to cell structures mediated by free-radicals, leading to the production of DNA double-strand breaks, which in turn lead to apoptosis, if not repaired [18][19][20]. However as our understanding of the effects of RT has increased it has been recognised that radiation has effects on the vascular system, the is rare in clinical practice [28].…”