ReACp53 可以抑制 p53 淀粉样蛋白的形成并挽救癌细胞系中的 p53 功能。
ReACp53 is an inhibitor of p53 amyloid formation.
Nearly half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state.
In vitro: Previous study found that ReACp53 could penetrates into HGSOC primary cancer cells and convert mutant p53 from a punctate state into soluble wild-type-like p53. ReACp53 could also induce cell-dycle arrest, cancer cell death, resulting in p53 Degradation. Moreover, ReACp53 induced quich cell death in human primary uterine fibroblasts transfected with a R175H p53 mutant. In addition, ReACp53 was found to be able to specifically reduce the cell viability and proliferation of cancer cells with mutant but not wild-type p53 [1].
In vivo: Animal study showed that i.p. administered ReACp53 could rapidly enter the systemic circulation and could be detected in the mouse serum at the 1-hr time point. In addition, ReACp53 could be detected in tumor tissue. In efficacy models, tumor volumes monitored daily suggested that only ReACp53-treated OVCAR3 xenografts shrank whereas vehicle-treated tumors grew more than doubled in size. Moreover, mutant p53-bearing tumors in the ReACp53-treated mice were 80%–90% smaller in weight than the control cohort, further confirming the ability of ReACp53 to inhibit tumor proliferation in vivo [1].
Clinical trial: Up to now, ReACp53 is still in the preclinical development stage.
Reference:
[1] Soragni A et al.? A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas. Cancer Cell. 2016 Jan 11;29(1):90-103.
Animal experiment: | Mice[1]In the minimal residual disease model, three cohorts of mice (n=3) are injected with a matrigel/OVCAR3 (p53 mutant) suspension on one flank and with a matrigel/MCF7 (WT p53) suspension on the other flank. Treatment is started the same day. In both models, the treatment phase consist of three weeks of daily IP injections with 15 mg/kg of ReACp53, sequence-scrambled control peptide or vehicle alone[1]. |
参考文献: [1]. Soragni A et al. A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas.Cancer Cell. 2016 Jan 11;29(1):90-103. | |
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