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Stem cells in radiotherapy
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Robert P. Coppes, Michael Baumann, Mechthild Krause, Richard P. Hill
Adult stem cells under normal circumstances are mostly quiescent residing in the G0 phase of the cell cycle, until cell loss requires them to proliferate. While this makes the study of DNA repair in stem cells in culture problematic, using in vivo long-term single-cell labelling and imaging techniques to track ASCs, but not their descendants, DNA repair in stem cells can be studied in vivo. Such studies have revealed several intriguing differences between ASCs and progenitor/differentiated cells. Quiescent stem cells have a low metabolic activity and often-high levels of anti-apoptotic proteins such as Bcl-2 and decreased production of reactive oxygen species (ROS) necessary for longevity. The use of glycolytic pathways for energy instead of mitochondrial respiration, the maintenance of a hypoxic niche, high levels of ABC transporters and the expression of BMI-1 in many ASCs may all contribute to a more radioresistant phenotype. ASCs are also intrinsically more efficient in base and nucleotide excision repair and repair single- and double-strand breaks better. This may relate to the fact that DNA damage checkpoints and several repair pathways are cell-cycle dependent. However, if ASCs accumulate DNA damage and are then forced to enter the cell cycle, the higher levels of DNA-PKs in ASCs lead primarily to repair by error-prone non-homologous end joining. This potentially results in ASC exhaustion, premature differentiation and senescence and reduced regenerative response, acquisition of mutations and predisposition to cancer (8).
Introduction to Telomere Biology
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Celia de Frutos, Pablo Bermejo-Álvarez
The chromosome ends display properties similar to DNA DSB and also telomeres contain a region of ssDNA (de Lange 2009). Both features make them prone to activate the DNA damage checkpoints that trigger the two signalling ways for DNA DSB: (1) ATM and 2) ATR. The activation of ATM or ATR results in cell cycle detention to avoid further DNA erosion (d’Adda di Fagagna et al. 2003). Apart from impeding the cell cycle blockage mediated by ATM or ATR, the chromosome ends must avoid the activation of the DSB repairing mechanisms: (1) HDR and (2) NHEJ. The activation of HDR would lead to a sequence exchange between two telomeres or one telomere and another part of the genome, resulting in chromosome rearrangements, terminal deletions or drastic changes in telomere length. Similarly, the activation of NHEJ would lead to terminal fusions resulting in dicentric chromosomes, which are unstable on mitosis. Telomeres must, therefore, avoid the activation of DSB signalling and DSB repair by avoiding DDR (d’Adda di Fagagna et al. 2004).
Therapeutic Targeting of the Melanoma Stem Cell Population
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
Keiran S.M. Smalley, Brijal Desai, Meenhard Herlyn
Although the past 40 years have seen many breakthroughs in the treatment of childhood leukemia and testicular cancer, there has been little tangible increase in the survival of patients with most metastatic solid tumors including melanoma, breast, colon, lung, and prostate cancers. The classical approaches to cancer therapy have relied upon killing the rapidly proliferating population of tumor cells through the generation of genotoxic stress, such as chemotherapy/radiation, or by using targeted agents that block the signaling pathways that drive tumor growth (26). The stem cell model posits that as the cancer stem cells cycle very slowly and express multiple drug transporter proteins, they are almost totally resistant to conventional anticancer therapies (27). Although these ideas are widely accepted in the field, data to confirm this hypothesis has only recently become available. It has been recently shown that growth of breast cancer cells under mammosphere culture conditions, which are thought to enrich for the stem cell population, leads to increased radiation resistance and less DNA damage, compared with similar cells grown as adherent cell cultures (28). Intriguingly, radiation treatment actually led to an increase in the percentage of the non-adherent CD24−/low/CD44+ cell population, suggesting that radiation treatment increases the size of the tumor-initiating cell pool (28). Similar results were also found in glioma, where the tumor-initiating population is defined through the cell surface expression of CD133+ (29). In these studies, the CD133+ glioma cell population was more resistant to radiation treatment than the CD133− population. Again, like in the breast cancer studies, it was shown that the CD133+ cell fraction expanded following radiation treatment and that this relatively small increase in the CD133+ population had very profound effects on the tumor growth rate (29). Comparison of DNA damage marker induction following radiation treatment showed that the CD133+ glioma cell population was able to activate the DNA damage checkpoints more efficiently than the CD133−, leading to a more radioresistant phenotype. Hints of a possible strategy to overcome this resistance came when it was shown that inhibition of the DNA damage responsive kinases CHK1 and CHK2 using pharmacological inhibitors sensitized the CD133+ cells to radiation (29).
Application of a novel multicomponent nanoemulsion to tumor therapy Based on the theory of “unification of drugs and excipients”
Published in Pharmaceutical Development and Technology, 2023
Quandong Li, Xinru Chen, Wen Lin, Xiaofeng Guo, Yan Ma
Cell cycle checkpoints have been used to monitor and regulate the progress of the cell cycle. The S and G2/M phases are used as DNA-damage checkpoints (Elledge 1996). We detected the cell cycle kinetics by FACS analysis. In comparison with the control, the group treated with TSE NEs and TSE-BJO NEs had an evidently increased proportion of HepG2 cells in G2/M phase observed in Figure 4 (p <0.001). The percentage of cells in G2/M phase for TSE-BJO NEs group was about twice as much as the untreated group. Although BJO NEs had fewer influence on the cell cycle, they could promote cell arrest in S phase and G2/M as combined with TSE. It suggests that the combination of the two drugs benefited cell cycle arrest.
Combining inhibition of immune checkpoints and PARP: rationale and perspectives in cancer treatment
Published in Expert Opinion on Therapeutic Targets, 2022
Martina Catalano, Luigi Francesco Iannone, Federica Cosso, Daniele Generali, Enrico Mini, Giandomenico Roviello
DNA repair is a fundamental process designed to identify and correct damage to the DNA molecules encoding genome, due to environmental factors and normal metabolic cellular processes. DNA damage activates a complex signaling cascade involving DNA damage checkpoints that, stopping the cell cycle, provide the cells with the needed time to repair the lesion or, if not achievable, to induce senescence and apoptosis [8]. Cellular signaling cascades activate three upstream kinases (ATM, ATR, and DNA-PKs) that phosphorylate the downstream kinases CHK1 and CHK2 which arrest the cell cycle in G1 and G2/S phases.
1,3-dimethyl-6-nitroacridine derivatives induce apoptosis in human breast cancer cells by targeting DNA
Published in Drug Development and Industrial Pharmacy, 2019
Qian Zhou, Hongshuai Wu, Chaoqun You, Zhiguo Gao, Kai Sun, Mingxin Wang, Fanghui Chen, Baiwang Sun
Recent studies show that acridine derivatives play antitumor activities by interfering with cell cycle [38]. DNA damage induced by anticancer agents may activate DNA damage checkpoints, which arrest cell cycle progression, trigger DNA damage repair, or lead to cell death [39].