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Reuther, Clemens; Heinzle, Vera; Noelting, Svenja; Herterich, Sabine; Hahner, Stefanie; Halilovic, Ensar; Jeay, Sebastien; Wuerthner, Jens U.; Prada, Elke Tatjana Aristizabal; Spoettl, Gerald; Maurer, Julian; Auernhamme, Christoph J. (2018): 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 p53(wild type) Neuroendocrine Tumor Cell Line GOT1. In: Neuroendocrinology, Vol. 106, No. 1: pp. 1-19
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Abstract

Background/Aims: 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 p53(wild 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. Methods: 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. Results: While p53 (wild type) GOT1 cells were sensitive to NVP-CGM097, p53(mutated) BON1 and p53(mutated) 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. Conclusions: MDM2 inhibition seems a promising novel therapeutic target in neuroendocrine tumors harboring p53(wild type). Further investigations should examine the potential role of MDM2 inhibitors in neuroendocrine tumor treatment.