China
Africa
Explore chapters and articles related to this topic
Structural and physiological aspects of cell death
Published in G. F. Wiegertjes, G. Flik, Host-Parasite Interactions, 2004
In free-radical-induced necrosis, the mechanism of intracellular energy depletion is not always obvious. It can be explained by metabolic exhaustion by the activity of ion pumps in addition to an inhibition of gycolysis or mitochondrial functions (Leist et al., 1999; Redegeld et al., 1990). Furthermore, excessive DNA damage causes poly (ADP-ribose) polymerase 1 (PARP-1) hyperactivation (reviewed by Chiarugi, 2002), an abundant nuclear enzyme involved in DNA-repair, DNA stability and transcriptional regulation. PARP-1 is activated by DNA strand breaks, and overactivation of PARP after cellular insults can lead to cell death caused by depletion of the enzyme’s substrate β-nicotinamide adenine dinucleotide (NAD+) and ATP. Caspases, in particular caspase-3 and -7, cleave PARP-1 and thus prevent the recruitment of the enzyme to sites of DNA damage (Cohen, 1997), a hallmark of apoptosis. Fibroblasts from PARP-deficient (PARP-/-) mice were protected from necrotic cell death and ATP depletion, which was induced in fibroblasts from PARP (+/+) mice upon hydrogen peroxide exposition (Ha and Snyder, 1999). In fibroblasts expressing caspase-resistant PARP, enhanced necrosis coupled with depletion of NAD+ and ATP was induced by treatment with tumour necrosis factor alpha. The PARP inhibitor 3-aminobenzamide prevented the NAD+ drop and concomitantly inhibited necrosis and elevated apoptosis (Herceg and Wang, 1999). Activation or cleavage of PARP is suggested to function as a molecular switch between apoptotic and necrotic modes of death receptor-induced cell death (Los et al., 2002).
Synthetic lethality on drug discovery: an update on cancer therapy
Published in Expert Opinion on Drug Discovery, 2020
M. Shahar Yar, Kashif Haider, Vivek Gohel, Nasir Ali Siddiqui, Ahmed Kamal
In the perspective of the treatment of cancer, PARP inhibitors originally proposed as chemosensitizers; PARP 1 has a well-defined role in DNA repair, and the PARP 1-deficient cells especially responsive to certain injure DNA compounds. In the early 1980s, 3-aminobenzamide shown to enhance the cytotoxic effects of DNA methylating agent of dimethyl sulfate and a variety of preclinical studies have shown that PARP inhibitors enhance the effects of temozolomide, another DNA methylating agent. The findings led to the clinical judgment of the PARP inhibitor along with temozolomide, with encouraging results in individuals with metastatic melanoma. Inhibition of PARP can amplify the effects of agents such as temozolomide by inhibiting base excision repair proteins, the main path to repair some DNA lesions produced by methylating agent. Additional combination therapies has also been suggested, especially PARP inhibitors with either radiotherapy or topoisomerase I inhibitor [32] and clinical trials examined the PARP inhibitor combination therapy with carboplatin, dacarbizine, irinotecan, topotecan or radiotherapy with temozolomide is ongoing. FDA approved PARP inhibitors include drugs niraparib (ovarian cancer), rucaparib (ovarian cancer), olaparib (prostate/ovarian/breast cancer), and drug in Phase 4 talazoparib (EMBRACA) [19] (Figure 4).
Anti-apoptotic effect of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase, against multiple organ damage induced by gamma irradiation in rats
Published in International Journal of Radiation Biology, 2018
Marwa M. El-Sheikh, Rania M. El-Hazek, Aiman S. El-Khatib, Mona A. El-Ghazaly
Radiotherapy is used at some stage in the treatment of around 50% of cancer patients. IR causes damage to normal tissues as well as inducing DNA breaks that are considered the most cytotoxic event. The exposure to IR causes that damage primarily via the generation of reactive oxygen species (ROS) (Virag and Szabo 2002; Azzam et al. 2012). Such destructive effect was found to stimulate the DNA nick-sensor enzyme, poly (ADP-ribose) polymerase (PARP) (Kiang et al. 2012). This process is accompanied by much consumption of PARP-1-substrate, NAD+ and consequently mitochondrial ATP to facilitate DNA repair and maintain the genomic integrity (Virag and Szabo 2002; Ba and Garg 2011). Benzamides, particularly the 3-aminobenzamide (3AB), inhibit PARP by interfering with the binding of NAD+ to the enzyme’s active site. In addition, 3AB deactivates the PARP by binding to DNA and thereby prevents the recognition of DNA breaks by the enzyme (Southan and Szabo 2003).