title: The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53wild type Neuroendocrine Tumor Cell Line GOT1.
abstract: The tumor suppressor p53 is depleted in many tumor cells by the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2) through MDM2/p53 interaction. A novel target for inhibiting p53 degradation and for causing reexpression of p53wild type is inhibition of MDM2. The small molecule NVP-CGM097 is a novel MDM2 inhibitor. We investigated MDM2 inhibition as a target in neuroendocrine tumor cells in vitro.
  
  
  
  Human neuroendocrine tumor cell lines from the pancreas (BON1), lung (NCI-H727), and midgut (GOT1) were incubated with the MDM2 inhibitor NVP-CGM097 (Novartis) at concentrations from 4 to 2,500 nM.
  
  
  
  While p53wild type GOT1 cells were sensitive to NVP-CGM097, p53mutated BON1 and p53mutated NCI-H727 cells were resistant to NVP-CGM097. Incubation of GOT1 cells with NVP-CGM097 at 100, 500, and 2,500 nM for 96 h caused a significant decline in cell viability to 84.9 ± 9.2% (p < 0.05), 77.4 ± 6.6% (p < 0.01), and 47.7 ± 9.2% (p < 0.01). In a Western blot analysis of GOT1 cells, NVP-CGM097 caused a dose-dependent increase in the expression of p53 and p21 tumor suppressor proteins and a decrease in phospho-Rb and E2F1. Experiments of co-incubation of NVP-CGM097 with 5-fluorouracil, temozolomide, or everolimus each showed additive antiproliferative effects in GOT1 cells. NVP-CGM097 and 5-fluorouracil increased p53 and p21 expression in an additive manner.
  
  
  
  MDM2 inhibition seems a promising novel therapeutic target in neuroendocrine tumors harboring p53wild type. Further investigations should examine the potential role of MDM2 inhibitors in neuroendocrine tumor treatment.
authors.affiliation: Department of Internal Medicine II, Campus Grosshadern, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Reuther
authors.forename: Vera
authors.initials: V
authors.lastname: Heinzle
authors.forename: Svenja
authors.initials: S
authors.lastname: Nölting
authors.forename: Sabine
authors.initials: S
authors.lastname: Herterich
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hahner
authors.forename: Ensar
authors.initials: E
authors.lastname: Halilovic
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jeay
authors.forename: Jens U
authors.initials: JU
authors.lastname: Wuerthner
authors.forename: Elke Tatjana
authors.initials: ET
authors.lastname: Aristizabal Prada
authors.forename: Gerald
authors.initials: G
authors.lastname: Spöttl
authors.forename: Julian
authors.initials: J
authors.lastname: Maurer
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Auernhammer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D007546:Isoquinolines; C000602644:NVP-CGM097; D010879:Piperazines; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005472:Fluorouracil
keywords: 5-Fluorouracil; Everolimus; GOT1; MDM2 inhibitor; NVP-CGM097; Neuroendocrine tumor; Temozolomide; p21; p53