Differential cytotoxicity of novel somatostatin and dopamine chimeric compounds on bronchopulmonary and small intestinal neuroendocrine tumor cell lines

• Published in: Cancer 2008-08, Vol.113 (4), p.690-700
• Main Authors: Kidd, Mark, Drozdov, Ignat, Joseph, Richard, Pfragner, Roswitha, Culler, Michael, Modlin, Irv
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - therapeutic use; antiproliferative agents; Biological and medical sciences; Bronchial Neoplasms - drug therapy; Cell Line, Tumor; Cell Proliferation - drug effects; Dopamine Agonists - therapeutic use; Drug Combinations; Humans; Intestinal Neoplasms - drug therapy; Intestine, Small; lanreotide; Lung Neoplasms - drug therapy; Medical sciences; neuroendocrine tumors; Neuroendocrine Tumors - drug therapy; octreotide; Octreotide - therapeutic use; Peptides, Cyclic - therapeutic use; Pneumology; Signal Transduction - drug effects; somatostatin; Somatostatin - analogs & derivatives; Somatostatin - therapeutic use; Tumors; Tumors of the respiratory system and mediastinum
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.23700

BACKGROUND. Survival rates for gastrointestinal (GI) and bronchopulmonary (BP) neuroendocrine tumors (NETs) have not significantly altered (overall 67%, 5‐year survival) in 30 years (1973‐2004), whereas the incidence has increased (∼ 1000%) in the same time frame. No effective or specific antineoplastic agent is available for treatment, although somatostatin analogs inhibit tumor secretion. Given the coexistence of somatostatin and dopamine regulatory receptors on NET cells, the antiproliferative efficacy as well as the signaling and transcriptional targets of their ligands were evaluated. METHODS. The cytotoxic effects of 12 somatostatin/dopamine compounds were evaluated in 3 NET cell lines, and real‐time polymerase chain reaction and enzyme‐linked immunoadsorbent assay studies were performed to delineate antiproliferative signaling pathways. RESULTS. The atypical BP‐NET, NCI‐H720, was most sensitive to the sst5 analog BIM23206 (half‐maximal concentration, 2.4 pM) and demonstrated similar sensitivity to lanreotide and the sst2 analog BIM23120. The typical BP‐NET, NCI‐H727, was most sensitive to BIM23120 (0.7 nM) and to the pan‐somatostatin receptor analog (BIM23A779). The GI‐NET, KRJ‐I, was most sensitive to sst2,5 analogs lanreotide (1 nM) and BIM23244 (7.4 nM). Lanreotide activated extracellular signal regulated kinase‐1/2 phosphorylation and p21WAF1/CIP1 transcription, but inhibited Ki‐67 transcription. NCI‐H720 was most sensitive to the sst2,5‐ and D2‐selective compound BIM23A761 (4.2 nM), as was NCI‐H727 (5.5 nM). KRJ‐I did not respond to any chimeric analog. BIM23A761 activated c‐Jun N‐terminal kinase signaling and caused inhibition of Ki‐67 transcription. P21WAF1/CIP1 transcription was activated only in NCI‐H727 cells. CONCLUSIONS. The different responses of each individual cell line suggested that NETs from different locations arising from different neuroendocrine cells may require cell‐specific antiproliferative agents based on the unique receptor profile of individual lesions. Cancer 2008. © 2008 American Cancer Society. The cytotoxic effects of 12 somatostatin/dopamine compounds were evaluated in 3 neuroendocrine tumor (NET) cell lines, and real‐time polymerase chain reaction and enzyme‐linked immunoadsorbent assay studies were performed to delineate antiproliferative signaling pathways. The different responses of each individual cell line suggested that NETs from different locations arising from different neuroendocrine cells may require cell‐