Abstract
Prolonged 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.
Highlights
Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms derived from neuroendocrine cells with a wide spectrum of clinical behavior [1]
We evaluated the direct effects of ketoconazole in adrenocorticotropic hormone (ACTH)-producing and non-ACTH-producing NET cell lines
We examined effects on proliferation, mRNA expression, and secretion by ketoconazole as monotherapy, as well as in combination with somatostatin analogs (SSA), the latter representing the recommended first-line therapy in non-functioning/functioning progressive G1/G2 NETs [31]
Summary
Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms derived from neuroendocrine cells with a wide spectrum of clinical behavior [1]. NETs can occur sporadically or as a result of hereditary predisposition syndromes [2]. Their capacity to secrete peptide hormones divides them in functioning and non-functioning tumors [1]. One of the most uncommonly secreted hormones is adrenocorticotropic hormone (ACTH) [3, 4], resulting in hypercortisolism and ectopic ACTH syndrome (EAS). In some cases, surgery is not possible or successful and in other cases, the source of ectopic ACTH is not identified [8, 9]. For these patients, medical treatment with steroidogenesis inhibitors including ketoconazole and bilateral adrenalectomy represents alternative therapeutic options [10–12]
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