School of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
School of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Nucl Med Biol. 2020 Nov-Dec;90-91:49-54. doi: 10.1016/j.nucmedbio.2020.09.004. Epub 2020 Sep 28.
I-labeled m-iodobenzylguanidine ([I]MIBG) has been used to treat neuroblastoma patients, but [I]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 [I]MIBG in neuroblastomas and improve accumulation by inhibition of the transporter in neuroblastomas.
[I]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 [I]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 [I]MIBG with and without probenecid in SK-N-SH-bearing mice.
[I]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. [I]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 [I]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.
[I]MIBG exports via MRP1 and MRP4 in neuroblastoma. The accumulation and tumor-to-blood or muscle ratios of [I]MIBG are improved by inhibition of MRPs with probenecid in neuroblastoma. ADVANCES IN KNOWLEDGE: [I]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 [I]MIBG accumulation.
碘代间碘苄胍([I]MIBG) 已被用于治疗神经母细胞瘤患者，但 [I]MIBG 可能会被三磷酸腺苷结合盒转运蛋白类似抗癌药物一样，立即从癌细胞中排出。本研究的目的是阐明神经母细胞瘤中 [I]MIBG 的外排机制，并通过抑制转运蛋白来提高其在神经母细胞瘤中的积累。
将 [I]MIBG 孵育在表达人有机阴离子转运多肽 (OATP)1B1、OATP1B3、OATP2B1、有机阴离子转运蛋白 (OAT)1 和 OAT2、有机阳离子转运蛋白 (OCT)1 和 OCT2 以及牛磺胆酸钠共转运蛋白的人胚肾 (HEK)293 细胞中，以及在表达 P-糖蛋白 (MDR1)、多药耐药相关蛋白 (MRP)1-4 或乳腺癌耐药蛋白的囊泡中，同时加入和不加入 MK-571 和丙磺舒。使用 SK-N-SH 神经母细胞瘤细胞系建立 [I]MIBG 的时间活性曲线，并测定多药耐药的转运蛋白表达。在携带 SK-N-SH 的小鼠中，用 [I]MIBG 与丙磺舒和不用丙磺舒进行生物分布和 SPECT 成像检查。
与模拟细胞相比，OAT1、OAT2、OCT1 和 OCT2 中的 [I]MIBG 摄取量明显更高。MK-571 和丙磺舒对 OCT1 和 OCT2 的摄取抑制作用很小。在 ATP 中，MRP1 或 MRP4 高表达的 [I]MIBG 摄取量明显高于 AMP，这些抑制剂将摄取量恢复到 AMP 相似的水平。在 SK-N-SH 细胞中研究 [I]MIBG 的时间活性曲线时，与对照相比，MDR1、MRP1、MRP4 和 MK-571 的高表达，或丙磺舒加载，在大多数孵育时间内，摄取量显著增加。与正常小鼠相比，携带 SK-N-SH 的小鼠的肿瘤与血液或肌肉的比值显著增加。
[I]MIBG 通过神经母细胞瘤中的 MRP1 和 MRP4 进行外排。在神经母细胞瘤中，用丙磺舒抑制 MRP 可提高 [I]MIBG 的积累和肿瘤与血液或肌肉的比值。
广泛用于治疗神经内分泌肿瘤，包括神经母细胞瘤的 [I]MIBG，通过神经母细胞瘤中的 MRP1 和 MRP4 进行排泄。
丙磺舒、OAT 和 MRP 抑制剂的加载可提高 [I]MIBG 的积累。
