Small-molecule modulators of p53 family signaling and antitumor effects in p53-deficient human colon tumor xenografts.
p53 deficiency is common in almost all human tumors and contributes to an aggressive chemo- or radiotherapy-resistant phenotype, therefore providing a target for drug development. Molecular targeting to restore wild-type p53 activity has been attempted in drug development and has led to the identification of CP-31398, PRIMA1, and the Nutlins. However, strategies targeting p53-activated transcriptional responses or p53 family member expression in p53-deficient tumors have yet to be explored. Here we demonstrate the use of noninvasive bioluminescence imaging in a high-throughput cell-based screen of small molecules that activate p53 responses and cell death in human tumor cells carrying a mutant p53. We isolated a number of small molecules that activate p53 reporter activity, increase expression of p53 target genes such as p21(WAF1) or death receptor 5 (KILLER/DR5) of TNF-related apoptosis-inducing ligand (TRAIL), and induce apoptosis in p53-deficient cells. Some of the compounds activate a p53 response by increasing p73 expression, and knockdown of transactivating isoforms of p73 by small interfering RNA reduces their induction of p53-responsive transcriptional activity. Some compounds do not induce significant p73 expression but induce a high p53-responsive transcriptional activity in the absence of p53. In vivo experiments demonstrate potent antitumor effects of selected compounds, using either HCT116/p53(-/-) or DLD1 human colon tumor xenografts. The results establish the feasibility of a cell-based drug screening strategy targeting the p53 transcription factor family of importance in human cancer and provide lead compounds for further development in cancer therapy.
Wang
Wenge
W
Department of Medicine (Hematology/Oncology), Institute for Translational Medicine and Therapeutics, Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Kim
Seok-Hyun
SH
El-Deiry
Wafik S
WS
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008163:Luminescent Measurements; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D009316:National Institutes of Health (U.S.); D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000145:classification / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D014481:United States; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D004247:DNA