A Chemical Modulator of p53 Transactivation that Acts as a Radioprotective Agonist

Abstract

Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives, that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses, including enhancing p21 induction and suppressing PUMA induction. This p53-modulating activity also influenced p53 and p53-target gene expression in unirradiated cells without inducing DNA damage. The specificity of 5CHQ for p53 and p21 was demonstrated by silencing the expression of each protein. These effects seem to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays. In addition, 5-chloro-8-methoxyquinoline itself had no antiapoptotic activity, indicating that the hydroxyl group at the 8-position is required for its antiapoptotic activity. We applied this remarkable agonistic activity to protecting the hematopoietic and gastrointestinal system in mouse irradiation models. The dose reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. 5CHQ effectively protected mouse epithelial stem cells from a lethal dose of abdominal irradiation. Furthermore, the specificity of 5CHQ for p53 in reducing the lethality induced by abdominal irradiation was revealed in -KO mice. These results indicate that the pharmacologic upregulation of radioprotective p53 target genes is an effective strategy for addressing the gastrointestinal syndrome.

The protective effects of XH‐105 against radiation‐induced intestinal injury

“…Many studies have shown that IR‐induced tissue damage increases the amount of apoptotic cells . Caspases are a family of genes important for maintaining homeostasis by regulating apoptosis and inflammation .…”

“…26,27 Under physiological conditions, epithelial homeostasis is maintained by proliferative cells in crypts, and the small intestinal crypt Many studies have shown that IR-induced tissue damage increases the amount of apoptotic cells. [31][32][33] Caspases are a family of genes important for maintaining homeostasis by regulating apoptosis and inflammation. 34 Caspases involved in apoptosis have been subclassified by their mechanism of action into initiator caspases (caspase-8 and -9) and executioner caspases (caspase-3, -6 and -7).…”

Development of p53-targeting drugs that increase radioresistance in normal tissues

“…However, we found that 5CHQ had a unique radioprotective activity during our evaluation of a series of 8-HQ derivatives. 5CHQ enhances the p53-mediated induction of antiapoptotic p21 and suppresses the induction of proapoptotic PUMA, which consequently leads to the prevention of p53-dependent cell death (2). The protective effect of 5CHQ on the mice bone marrow death after 7.5 Gy-TBI had a limited effect, with half of the mice being rescued.…”

“…Therefore, our goal is to develop a normal tissue-selective radioprotective agent that permits a good value of dose reduction factor (DRF; the fold change in irradiation dose to produce a given level of biological effect). We initially set the target value of DRF to 1.3 and more, because a value of 1.3 is excellent protection activity comparable to DRFs achieved by the radioprotective agents developed so far (2,3).…”

Refining Radiation for the Next Century

“…Both the bone marrow and the gastrointestinal tract are highly sensitivity to IR toxicity. Morita and colleagues (10) found that 5-chloro-8-quinolinol (5CHQ), albeit at high concentrations, shifted p53 transactivation activity from proapoptotic to antiapoptotic by enhancing p21 induction and suppressing PUMA induction. This p53-modulating effect seemed to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays.…”