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SGT-53: A Novel Nanomedicine Capable of Augmenting Cancer Immunotherapy
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Joe B. Harford, Sang-Soo Kim, Kathleen F. Pirollo, Antonina Rait, Esther H. Chang
Indirect restoration of p53 functions has also been attempted by aiming at other components of the p53 network [54–56, 89]. It has long been appreciated that alterations in proteins other than p53 can influence p53 functions. Perhaps the most extensively studied are MDM2 and MDMX, two related negative regulators of p53 activity that have ubiquitin ligase activity [90–92]. In response to DNA damage, phosphorylation events inhibit the interaction of p53 with MDM2/MDMX resulting in p53 stabilization with consequent activation of downstream transcriptional targets [93, 94]. Because MDM2/MDMX are negative regulators of p53, overexpression of MDM2/MDMX results in loss of p53 function that can result in oncogenesis [95–97]. In those instances wherein p53 function is lost in a tumor through overexpression of its negative regulators, interventions that down-modulate these regulators or interfere with their interaction with p53 would be expected to restore p53 function for tumor suppression. Such molecules are under study as cancer therapeutics [96, 98–100], but their usefulness may be limited to that subset of cancers wherein wild-type p53 is inhibited by MDM2/MDMX overexpression.
Combination treatment with auranofin and nutlin-3a induces synergistic cytotoxicity in breast cancer cells
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Dong-Jin Ye, Yeo-Jung Kwon, Hyoung-Seok Baek, Eunah Cho, Tae-Uk Kwon, Young-Jin Chun
p53, a protein encoded by TP53 gene is a well-known tumor-suppressing transcription factor. During intracellular stress conditions such as DNA damage, hypoxia, and oncogene activation, p53 expression is induced leading to diverse cellular responses including cell cycle arrest and apoptosis (Lee et al. 2016; Wang, Simpson, and Brown 2015). As p53-mediated intracellular signaling is a crucial factor in inhibiting tumor growth, several studies examined the possibility to develop efficient breast cancer therapies using p53 as a therapeutic target by implementing different approaches including wild-type p53 activation, mutant p53 reactivation, or p53-based vaccines (Hong et al. 2014). In many cases of breast cancer, p53-mediated mechanisms such as DNA damage-induced cell death and cell cycle regulation are often not activated due to overexpression of mouse double minute 2 homolog (MDM2) and MDMX. These protooncogenes function as E3 ubiquitin ligases and produce degradation of p53 (Wang and Yan 2011). Thus, one of the conventional therapeutic strategies for breast cancer treatment is the prevention of wild-type p53 from undergoing proteasomal degradation by MDM2 and efficiently retrieving the p53 pathway in the intra-tumoral environment (Turner et al. 2013).