[131I]MIBG exports via MRP transporters and inhibition of the MRP transporters improves accumulation of [131I]MIBG in neuroblastoma

• Published in: Nuclear medicine and biology Vol. 90-91; pp. 49 - 54
• Main Authors: Kobayashi, Masato, Mizutani, Asuka, Nishi, Kodai, Muranaka, Yuka, Nishii, Ryuichi, Shikano, Naoto, Nakanishi, Takeo, Tamai, Ikumi, Kleinerman, Eugenie S., Kawai, Keiichi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2020; Elsevier BV
• Subjects: 3-Iodobenzylguanidine - metabolism; [123/131I]MIBG; Accumulation; Adenosine triphosphate; AMP; Animals; Anions; Antineoplastic drugs; Antitumor agents; ATP; Bile; Biological Transport; Blood; Breast cancer; Cell Line, Tumor; Drug resistance; Efflux; Efflux transporter; Exports; Glycoproteins; HEK293 Cells; Humans; Inhibitors; Kidneys; Material requirements planning; MDR1 protein; Mice; MRP; Multidrug resistance; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - metabolism; Muscles; Neuroblastoma; Neuroblastoma - diagnostic imaging; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroendocrine tumors; Oct-2 protein; Organic anion transporting polypeptide; Organic cation transporter; P-Glycoprotein; Polypeptides; Probenecid; Propionates; Proteins; Quinolines - pharmacology; Single photon emission computed tomography; Tissue Distribution; Tumors; Vesicles; MRP; Neuroblastoma; Efflux transporter; [123/131I]MIBG; Probenecid; [(123/131)I]MIBG
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2020.09.004

131I-labeled m-iodobenzylguanidine ([131I]MIBG) has been used to treat neuroblastoma patients, but [131I]MIBG may be immediately excreted from the cancer cells by the adenosine triphosphate binding cassette transporters, similar to anticancer drugs. The purpose of this study was to clarify the efflux mechanism of [131I]MIBG in neuroblastomas and improve accumulation by inhibition of the transporter in neuroblastomas.
[131I]MIBG was incubated in human embryonic kidney (HEK)293 cells expressing human organic anion transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, organic anion transporter (OAT)1 and OAT2, organic cation transporter (OCT)1 and OCT2, and sodium taurocholate cotransporting polypeptide, and in vesicles expressing P-glycoprotein (MDR1), multidrug resistance associated protein (MRP)1–4, or breast cancer resistance protein with and without MK-571 and probenecid (MRP inhibitors). Time activity curves of [131I]MIBG with and without MK-571 and probenecid were established using an SK-N-SH neuroblastoma cell line, and transporter expression of multiple drug resistance was measured. Biodistribution and SPECT imaging examinations were conducted using [123I]MIBG with and without probenecid in SK-N-SH-bearing mice.
[131I]MIBG uptake was significantly higher in OAT1, OAT2, OCT1, and OCT2 than in mock cells. Uptake via OCT1 and OCT2 was little inhibited by MK-571 and probenecid. [131I]MIBG uptake into vesicles that highly expressed MRP1 or MRP4 was significantly higher in ATP than in AMP, and these inhibitors restored uptake to levels similar to that in AMP. Examining the time activity curves for [131I]MIBG in SK-N-SH cells, higher expressions of MDR1, MRP1, MRP4, and MK-571, or probenecid loading produced significantly higher uptake than in control at most incubation times. The ratios of tumors to blood or muscle in SK-N-SH-bearing mice were significantly increased by probenecid loading in comparison with normal mice.
[131I]MIBG exports via MRP1 and MRP4 in neuroblastoma. The accumulation and tumor-to-blood or muscle ratios of [131I]MIBG are improved by inhibition of MRPs with probenecid in neuroblastoma.
[131I]MIBG, widely used for treatment of neuroendocrine tumors including neuroblastoma, is excreted via MRP1 and MRP4 in neuroblastoma.
Loading with probenecid, OAT, and MRP inhibitors improves [131I]MIBG accumulation.