A subset of CB002 xanthine analogs bypass p53-signaling to restore a p53 transcriptome and target an S-phase cell cycle checkpoint in tumors with mutated-p53

eLife

Nagib Ahsan¹  John Santiago²  David T Dicker³  Lanlan Zhou³  Xiaobing Tian³  Liz Hernandez Borrero³  Wafik S El-Deiry⁴  Jennifer Sanders⁵  Avital Lev⁶ 

[1] COBRE Center for Cancer Research Development, Proteomics Core Facility, Rhode Island Hospital, Providence, United States;Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States;Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, United States;The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States;Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States;Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, United States;Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, United States;Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, United States;The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States;Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States;Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, United States;Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, United States;Hematology-Oncology Division, Department of Medicine, Rhode Island Hospital and Brown University, Providence, United States;The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States;Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States;Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, United States;Department of Pediatrics, The Warren Alpert Medical School, Brown University, Providence, United States;The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States;Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States;Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, United States;

关键词: p53;    cancer;    therapy;    xanthines;    CB002;    noxa;    Human;   

DOI  :  10.7554/eLife.70429

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY