title: Meta-iodobenzylguanidine induces growth inhibition and apoptosis of neuroendocrine gastrointestinal tumor cells.
abstract: Neuroendocrine gastrointestinal tumors take up, decarboxylate and store large amounts of monoamines. Radioactive-labeled monoamines like the norepinephrine analogue meta-iodobenzylguanidine (MIBG) have been used for the imaging of neuroendocrine tumors for many years. MIBG is selectively taken up via norepinephrine transporters (NETs) localized in the plasma membrane of neuroendocrine gastrointestinal tumor cells and thereby offers the possibility for specific and innovative therapeutic approaches. We investigated the antiproliferative, cytotoxic, cell cycle-arresting and apoptosis-inducing effects of MIBG in the neuroendocrine gastrointestinal tumor cell line STC-1 and for control in the nonneuroendocrine colorectal cancer cell line HT-29. RT-PCR revealed the expression of NET in STC-1 but not in HT-29 cells. MIBG dose-dependently induced cytotoxicity and growth inhibition of STC-1 cells. It potently induced apoptosis in STC-1 cells as assessed by changes in the mitochondrial membrane potential, activation of caspase-3 and DNA fragmentation. Moreover, MIBG altered the expression of several genes involved in proliferation, apoptosis and stress responses as shown by cDNA arrays. In contrast, neither cytotoxicity, nor growth inhibition nor induction of apoptosis were detected in response to MIBG in the NET-deficient colorectal cancer cell line HT-29. Our data show that MIBG induces growth inhibition and apoptosis in neuroendocrine gastrointestinal tumor cells. MIBG did not arrest the cell cycle in either cell line. Thus, monoamine transporters in the plasma membrane of neuroendocrine gastrointestinal tumor cells are promising targets for innovative and specific treatment strategies of these tumors.
authors.affiliation: Medical Clinic I, University Hospital Benjamin Franklin, Free University of Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
authors.forename: Andreas P
authors.initials: AP
authors.lastname: Sutter
authors.forename: Nikolai I
authors.initials: NI
authors.lastname: Beck
authors.forename: Bettina
authors.initials: B
authors.lastname: Barthel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Maaser
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jockers-Scherübl
authors.forename: Martin
authors.initials: M
authors.lastname: Zeitz
authors.forename: Hans
authors.initials: H
authors.lastname: Scherübl
mesh_terms: D019797:3-Iodobenzylguanidine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D009363:Neoplasm Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493227:SLC6A2 protein, human; D027981:Symporters; D019797:3-Iodobenzylguanidine; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases