BIM-23A760 influences key functional endpoints in pituitary adenomas and normal pituitaries: molecular mechanisms underlying the differential response in adenomas.
Chimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D2receptors-agonist, have emerged as promising new approaches to treat pituitary adenomas. However, information on direct in vitro effects of BIM-23A760 in normal and tumoral pituitaries remains incomplete. The objective of this study was to analyze BIM-23A760 effects on functional parameters (Ca2+signaling, hormone expression/secretion, cell viability and apoptosis) in pituitary adenomas (n = 74), and to compare with the responses of normal primate and human pituitaries (n = 3-5). Primate and human normal pituitaries exhibited similar sst2/sst5/D2 expression patterns, wherein BIM-23A760 inhibited the expression/secretion of several pituitary hormones (specially GH/PRL), which was accompanied by increased sst2/sst5/D2 expression in primates and decreased Ca2+concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca2+concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca2+signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D2compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D2expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760.
Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 14004 Cordoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Cordoba; 14004 Cordoba, Spain.|Hospital Universitario Reina Sofía (HURS); 14004 Cordoba, Spain.|CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn); 14004 Cordoba, Spain.|Campus de Excelencia Internacional Agroalimentario (ceiA3); 14004 Cordoba, Spain.
Alejandro
A
Ibáñez-Costa
Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 14004 Cordoba, Spain.|Hospital Universitario Reina Sofía (HURS); 14004 Cordoba, Spain.
Laura M
LM
López-Sánchez
Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 14004 Cordoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Cordoba; 14004 Cordoba, Spain.|Hospital Universitario Reina Sofía (HURS); 14004 Cordoba, Spain.|CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn); 14004 Cordoba, Spain.|Campus de Excelencia Internacional Agroalimentario (ceiA3); 14004 Cordoba, Spain.
Manuel D
MD
Gahete
Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 14004 Cordoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Cordoba; 14004 Cordoba, Spain.|Hospital Universitario Reina Sofía (HURS); 14004 Cordoba, Spain.|CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn); 14004 Cordoba, Spain.|Campus de Excelencia Internacional Agroalimentario (ceiA3); 14004 Cordoba, Spain.
Esther
E
Rivero-Cortés
Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 14004 Cordoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Cordoba; 14004 Cordoba, Spain.|Hospital Universitario Reina Sofía (HURS); 14004 Cordoba, Spain.|CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn); 14004 Cordoba, Spain.|Campus de Excelencia Internacional Agroalimentario (ceiA3); 14004 Cordoba, Spain.
Mari C
MC
Vázquez-Borrego
Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 14004 Cordoba, Spain.|Hospital Universitario Reina Sofía (HURS); 14004 Cordoba, Spain.|Service of Endocrinology and Nutrition, IMIBIC, HURS, 14004 Cordoba, Spain.
María A
MA
Gálvez
Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 14004 Cordoba, Spain.|Hospital Universitario Reina Sofía (HURS); 14004 Cordoba, Spain.|Service of Neurosurgery, HURS, 14004 Cordoba, Spain.
Andrés
A
de la Riva
Metabolism and Nutrition Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), 41013 Seville, Spain.
Eva
E
Venegas-Moreno
Department of Morphological Sciences, University of Cordoba, 14004 Cordoba, Spain.
Luis
L
Jiménez-Reina
Endocrinology and Nutrition Unit, Complejo Hospitalario de Jaén, 23007 Jaén, Spain.
Alberto
A
Moreno-Carazo
Service of Endocrinology and Nutrition, Hospital Clínico Universitario Virgen de la Victoria, 29010 Málaga, Spain.
Francisco J
FJ
Tinahones
Service of Endocrinology and Nutrition, Hospital Clínico Universitario Virgen de la Victoria, 29010 Málaga, Spain.
Silvia
S
Maraver-Selfa
Department of Pathology, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain.
Miguel A
MA
Japón
Department of Endocrinology and Nutrition, Carlos Haya Hospital, 29010 Málaga, Spain.
Juan A
JA
García-Arnés
Metabolism and Nutrition Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), 41013 Seville, Spain.
Alfonso
A
Soto-Moreno
Department of Endocrinology, Hospital Sant Pau, Centre for Biomedical Research on Rare Diseases (Centro de Investigación Biomédica en Red de Enfermedades Raras Unit 747) Autonomous University of Barcelona; 08035 Barcelona Spain.
Susan M
SM
Webb
Department of Medicine, University of Illinois at Chicago, Jesse Brown Veterans Affairs Medical Center, Research and Development Division, Chicago, Illinois, USA.
Rhonda D
RD
Kineman
IPSEN Bioscience, Cambridge, 02142 Massachusetts, USA.
Michael D
MD
Culler
Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 14004 Cordoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Cordoba; 14004 Cordoba, Spain.|Hospital Universitario Reina Sofía (HURS); 14004 Cordoba, Spain.|CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn); 14004 Cordoba, Spain.|Campus de Excelencia Internacional Agroalimentario (ceiA3); 14004 Cordoba, Spain.
Justo P
JP
Castaño
Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 14004 Cordoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Cordoba; 14004 Cordoba, Spain.|Hospital Universitario Reina Sofía (HURS); 14004 Cordoba, Spain.|CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn); 14004 Cordoba, Spain.|Campus de Excelencia Internacional Agroalimentario (ceiA3); 14004 Cordoba, Spain.
Raúl M
RM
Luque
D000236:Adenoma / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D002470:Cell Survival; D002478:Cells, Cultured; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D005089:Exocytosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010215:Papio; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology
D018491:Dopamine Agonists; D011954:Receptors, Dopamine; D017481:Receptors, Somatostatin; D013004:Somatostatin; C531242:TBR-760; D004298:Dopamine