title: Increased uptake of [¹²³I]meta-iodobenzylguanidine, [¹⁸F]fluorodopamine, and [³H]norepinephrine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors.
abstract: [¹³¹I]meta-iodobenzylguanidine ([¹³¹I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [¹²³I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [(18)F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1 ± 3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9 ± 0.6%; P<0.001). Biodistribution analysis after inhibitors treatment confirmed the PET results. The uptake of [(123)I]MIBG was significantly increased in liver metastases 9.5 ± 1.1% compared to 3.19 ± 0.4% in untreated control liver metastases (P<0.05). We found that HDAC inhibitors caused an increase in the amount of norepinephrine transporter expressed in tumors. HDAC inhibitors may enhance the therapeutic efficacy of [(131)I]MIBG treatment in patients with advanced malignant pheochromocytoma and paraganglioma.
authors.affiliation: Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 1E-3140, 10 Center Drive MSC-1109, Bethesda, Maryland 20892-1109, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Martiniova
authors.forename: Shiromi M
authors.initials: SM
authors.lastname: Perera
authors.forename: Frederieke M
authors.initials: FM
authors.lastname: Brouwers
authors.forename: Salvatore
authors.initials: S
authors.lastname: Alesci
authors.forename: Mones
authors.initials: M
authors.lastname: Abu-Asab
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Marvelle
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: David
authors.initials: D
authors.lastname: Thomasson
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Richard
authors.initials: R
authors.lastname: Kvetnansky
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Tischler
authors.forename: James C
authors.initials: JC
authors.lastname: Reynolds
authors.forename: Antonio Tito
authors.initials: AT
authors.lastname: Fojo
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D019797:3-Iodobenzylguanidine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000310:Adrenal Gland Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D004298:Dopamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009638:Norepinephrine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010673:Pheochromocytoma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015854:Up-Regulation
chemical_list: D005462:Fluorine Radioisotopes; D056572:Histone Deacetylase Inhibitors; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D019797:3-Iodobenzylguanidine; C029253:6-fluorodopamine; D004298:Dopamine; D009638:Norepinephrine