Herrera-Martinez, Aura DFeelders, Richard Ade Herder, Wouter WCastaño, Justo PGalvez Moreno, Maria AngelesDogan, Fadimevan Dungen, Rosannavan Koetsveld, PeterHofland, Leo J2023-01-252023-01-252019-03-28Herrera-Martínez AD, Feelders RA, de Herder WW, Castaño JP, Gálvez Moreno MÁ, Dogan F, et al. Effects of Ketoconazole on ACTH-Producing and Non-ACTH-Producing Neuroendocrine Tumor Cells. Horm Cancer. 2019 Jun;10(2-3):107-119http://hdl.handle.net/10668/13981Prolonged remission of hypercortisolism with steroidogenesis inhibitors has been described in patients with ectopic adrenocorticotropic hormone (ACTH) syndrome. The anti-proliferative and pro-apoptotic effect of ketoconazole in human cancer cells was previously suggested. The aim of this study was to explore the effects of ketoconazole on ACTH-producing and non-ACTH-producing neuroendocrine tumor (NET) cell lines. The effects of ketoconazole alone, and in combination with somatostatin analogs, were evaluated in two human cell lines: DMS-79 (ectopic ACTH-producing small cell lung carcinoma) and BON-1 (human pancreatic NET). Total DNA measurement, apoptosis, cell cycle, chromogranin A (CgA)/proopiomelanocortin (POMC) expression by qRT-PCR, serotonin, CgA, and ACTH secretion assays were performed. In both cell lines, ketoconazole significantly suppressed cell growth and colony formation in a dose and time-dependent manner. The effect in DMS-79 was primarily cytotoxic, while it was more apoptotic in BON-1 cells. Ketoconazole also induced increase in G0/G1 phase in both cell lines and arrest in phase G2/M of BON-1 cells. Ketoconazole did not affect the secretion of serotonin, CgA, ACTH, or the mRNA expression of CgA and POMC. Decreased serotonin secretion was observed after the combination treatment with pasireotide. These results suggest a direct effect of ketoconazole on cell proliferation, apoptosis, and cell cycle in both ACTH- and non-ACTH-producing NET cells.enAttribution 4.0 International Licensehttp://creativecommons.org/licenses/by/4.0/Combined therapyKetoconazoleNeuroendocrine tumorsProliferationSecretion14-alpha demethylase inhibitorsAdrenocorticotropic hormoneApoptosisCell cycleCell line, tumorCell proliferationChromogranin AHumansKetoconazoleNeuroendocrine tumorsPancreatic neoplasmsPro-opiomelanocortinSerotoninSmall cell lung carcinomaSomatostatinresearch article31102172open accessCarcinoma pulmonar de células pequeñasCetoconazolCromogranina AHormona adrenocorticotrópicaLínea celular tumoralNeoplasias pancreáticasProliferación celularSomatostatinaTumores neuroendocrinos10.1007/s12672-019-00361-61868-8500https://link.springer.com/content/pdf/10.1007/s12672-019-00361-6.pdf