title: Small Molecule Inhibition of MDM2-p53 Interaction Augments Radiation Response in Human Tumors.
abstract: MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of γH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/or autophagic cell death. Several molecules involved in senescence, autophagy, and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM, and BAX. In vivo xenograft studies confirmed more potent antitumor and antiangiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Lauryn R
authors.initials: LR
authors.lastname: Werner
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Shyhmin
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: David M
authors.initials: DM
authors.lastname: Francis
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Armstrong
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Fang
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Chunrong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Gopal
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Oncology Research Amgen, Inc., Thousand Oaks, California.
authors.forename: Jude
authors.initials: J
authors.lastname: Canon
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. harari@humonc.wisc.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D010881:Piperidones / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C588087:2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; D000085:Acetates; D000970:Antineoplastic Agents; D010881:Piperidones; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2