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Molecular Biology and Gene Therapy
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
Restoring the function of a key cellular gene whose dysfunction has resulted in cancer progression is a major goal of gene therapy. The most common mutations of key genes in squamous cell cancer of the head and neck are p53 and p16. p53 plays a role in triggering cell death in many different pathways involving apoptosis. Gendicine®, a drug with modified adenovirus harbouring p53 gene, was approved in China in 2004, becoming the first gene therapy approved for clinical use in humans. However, the western version of Ad-p53 (Advexin®) for the treatment of head and neck cancer was refused approval by the U. S. Food and Drug Administration in 2008.
Genes and heredity in breast cancer
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
Modifications of oncogenes and suppressor genes do not necessarily cause cancer. Fortunately, when DNA is damaged, p53 arrests the cell cycle and activates appropriate mechanisms of repair of DNA; if the damage cannot be fixed, again p53 plays a key role in driving the cell towards apoptosis. On the other hand, with a malfunction of the DNA repair genes or of p53, mutations become permanent, the cell survives and divides, and the error is passed on to its descendants.
The Role of Nanoparticles in Cancer Therapy through Apoptosis Induction
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Marveh Rahmati, Saeid Amanpour, Hadiseh Mohammadpour
Nanoparticles (NPs) can induce oxidative stress in cells through diverse mechanisms: first, by a direct generation of ROS; second, by an indirect generation of ROS and reactive nitrogen species (RNS) through stimulating inflammatory cells [51]; third, by the indirect changes in mitochondrial integrity through NADPH oxidase or cellular calcium homeostasis; and last, by ROS generation through releasing ions or soluble compounds [45]. Any mechanism that leads to ROS production ultimately leads to damage to DNA and proteins as well as destruction of organelles such as mitochondria. The damaged mitochondria leads to the activation of apoptosis [54, 60]. The main operation of ROS in various cellular mechanisms is involved in cell cycle regulation, proliferation, self-renewal, differentiation, and apoptosis. The primary function of p53 as a tumor suppressor, upon DNA damage, is to induce cell cycle arrest and to repair the damage. If the damage cannot be repaired, apoptosis is initiated [38].
Protective mechanism of a novel aminothiol compound on radiation-induced intestinal injury
Published in International Journal of Radiation Biology, 2023
Xinxin Wang, Renbin Yuan, Longfei Miao, Xuejiao Li, Yuying Guo, Hongqi Tian
H2AX histones are important proteins in DNA synthesis. When the DNA double strand is broken, the C terminus serine is phosphorylated and changes H2AX into γ-H2AX (Shiloh 2003; Han et al. 2011). Excess ROS produced by radiation can damage biomolecules in human cells. The p53 protein will be activated to support DNA repair when the cells cannot be effectively repaired (Leibowitz et al. 2011; Islam 2017). When the DNA cannot be repaired, p53 will combine with Bax to induce cell apoptosis. In this study, compared to the control, the expression of γH2AX protein, p53 protein and Bax protein in the small intestinal sections was dramatically increased after ABI exposure. However, in the intestines of mice pretreated with compound 8, levels of expression of the γ-H2AX protein, p53 protein and Bax protein clearly decreased. These results indicate that compound 8 can reduce DNA damage and intestinal damage induced by ionizing radiation, and it may suppress radiation-induced apoptosis via the p53 pathway.
An overview of novel therapies in advanced clinical testing for acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Sangeetha Venugopal, Zhuoer Xie, Amer M. Zeidan
Apoptotic pathway can be targeted extrinsically by disrupting the p53-Mouse double minute 2 homolog (MDM2) interaction [80]. p53 is a tumor suppressor protein, whose activation may trigger apoptosis due to cellular stress and DNA damage. Under normal conditions, p53 homeostasis is tightly regulated and p53 undergoes proteasomal degradation by the E3 ubiquitin-protein ligase MDM2 [81]. In AML with wild type TP53, MDM2 overexpression results in enhanced degradation of p53 which confers immortality to the leukemic blasts. Therefore, targeting MDM2 appears attractive as it will potentially restore the activity of wild type p53 and the ensuing apoptotic machinery. In that vein, several agents that disrupt p53-MDM2 interaction, including idasanutlin and milademetan, have been evaluated in patients with AML [81].
p53 Missense Mutation is Associated with Immune Cell PD-L1 Expression in Triple-Negative Breast Cancer
Published in Cancer Investigation, 2022
Ai-Yan Xing, Long Liu, Ke Liang, Bin Wang
TP53 is an important suppressor gene that plays a key role in physiological processes. When the TP53 gene is mutated, it loses its regulatory effect on cell growth, apoptosis, and DNA damage repair due to its spatial conformation changes, which may lead to tumorigenesis (22). Kim et al. found a worse prognosis of patients with TP53 mutation and high expression in TNBC (23). By MSK database, the Kaplan–Meier analysis showed a reduced overall survival in p53 mutation group, compared with p53 wildtype group. Both results suggested that p53 mutation might be a potential predictive marker of TNBC. p53 mutants recently have become a new target for cancer therapy. For example, Synnott et al. found that COTI-2, a third-generation thiosemicarbazone, acts by reactivating mutant p53 to its wild form and inhibits tumor cell growth in TNBC (24).