Endocrine Abstracts (2017) 49 EP182 | DOI: 10.1530/endoabs.49.EP182

Effects of ketoconazole on ACTH-producing and non ACTH-producing neuroendocrine tumor cells

Aura D Herrera-Martínez2,3, Richard Feelders1, Justo Castaño2,4, Fadime Dogan1, Peter van Koetsveld1 & Leo Hofland1

1Department of Internal Medicine, Division of Endocrinology Erasmus University Medical Center, Rotterdam, The Netherlands; 2Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain; 3Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córdoba, Spain; 4Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain.

Prolonged spontaneous remission of hypercortisolemia in ectopic ACTH syndrome after long-term treatment with steroidogenesis inhibitors has been described. Direct drug effect on the adrenal glands, effects on tumoral ACTH secretion and/or POMC gene expression have been suggested. Medical treatment could be used for symptoms, but also for disease control.

Materials and methods: In human BON-1 and DMS-79 cells, we have evaluated the effects of ketoconazole on cell growth, apoptosis, cell cycle, LDH production, POMC/chromogranin-A mRNA expression and ACTH/serotonin secretion.

Results: In the BON-1 cells, ketoconazole significantly suppressed cell growth in a dose and time-dependent manner. Maximal inhibitory effects by 10 μM ketoconazole were 41 and 95% after 3 and 7 days (P<0.0001); the ratio LDH/DNA after 3 days was increased. The IC50 value of growth inhibition was 7.8 μM after 7 days of treatment. Ketoconazole also induced a significant G1-phase arrest accompanied by a decrease in S-phase and G2-phase, as well as a significant increase in early and late apoptosis (P<0,01), confirmed using an ELISA method. Ketoconazole (up to 10 μM) did not significantly affect the chromogranin-A expression or serotonin secretion (corrected for cell number). DMS-79 cells are less sensitive to ketoconazole, with maximally inhibitory effects by 50 μM ketoconazole of 44 and 94% after 3 and 7 days of treatment (P<0.0001). The IC50 value of the growth inhibitory effect was 15 μM after 7 days of treatment. The highest ketoconazole concentration (50 μM) tested induced a significant G1-phase arrest (P<0.001), increased number of dead cells (P<0,001) without significant effect on early/late apoptosis, increased total apoptosis (ELISA; P<0.0001), as well as the LDH/DNA (P<0.001). Ketoconazole up to 10 μM suppressed ACTH secretion (P<0.01). POMC expression did not show significant changes.

Conclusions: These results suggest a potential direct effect of ketoconazole on cell proliferation, apoptosis and cell cycle in ACTH- and non-ACTH producing NET cells. Additional studies are required to confirm and extend these results.

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