Abstract
Mutations in TP53 occur commonly in the majority of human tumors and confer aggressive tumor phenotypes, including metastasis and therapy resistance. CB002 and structural-analogs restore p53 signaling in tumors with mutant-p53 but we find that unlike other xanthines such as caffeine, pentoxifylline, and theophylline, they do not deregulate the G2 checkpoint. Novel CB002-analogs induce pro-apoptotic Noxa protein in an ATF3/4-dependent manner, whereas caffeine, pentoxifylline, and theophylline do not. By contrast to caffeine, CB002-analogs target an S-phase checkpoint associated with increased p-RPA/RPA2, p-ATR, decreased Cyclin A, p-histone H3 expression, and downregulation of essential proteins in DNA-synthesis and DNA-repair. CB002-analog #4 enhances cell death, and decreases Ki-67 in patient-derived tumor-organoids without toxicity to normal human cells. Preliminary in vivo studies demonstrate anti-tumor efficacy in mice. Thus, a novel class of anti-cancer drugs shows the activation of p53 pathway signaling in tumors with mutated p53, and targets an S-phase checkpoint.
Highlights
Tumor suppressor p53 responds to cell stress signals from DNA damage, oncogene activation, oxidative stress, and hypoxia
We investigated the capability of a set of the CB002-analogs to induce apoptosis as indicated by Propidium Iodide (PI) staining sub-G1 population
We describe a novel class of anti-tumor agents with a unique mechanism of action involving restoration of p53 pathway signaling, independently of p53, in tumors with mutated-p53 and characteristics of an S-phase checkpoint
Summary
Tumor suppressor p53 responds to cell stress signals from DNA damage, oncogene activation, oxidative stress, and hypoxia. Upon activation by posttranslational modifications and oligomerization, p53 signals cell cycle arrest, apoptosis, or DNA repair, according to the extent of the cellular stress, thereby controlling cell fate and preventing tumorigenesis (Riley et al, 2008). The mutated p53 protein results in loss-of-function but oligomerization can act in a dominant-negative fashion with regard to the remaining wild-type p53 allele. Patients whose tumors carry p53 mutations have a poor prognosis and decreased overall survival (Wattel et al, 1994)
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