Zotarolimus(ABT-578) is an immunosuppressant that inhibits immunophilin FKBP12 binding with an IC50 of 2.8±0.16nM[1]. Zotarolimus binds to the immunoaffinity protein FKBP12 to form the Zotarolimus-FKBP12 complex, which inhibits mammalian target of rapamycin (mTOR) to regulate intracellular metabolism[2]. Zotarolimus has been widely used in the development of novel drug-eluting stents to prevent coronary restenosis[3].
In vitro, Zotarolimus treatment for 48h inhibited human coronary artery smooth muscle cell (HCASMC) proliferation, with an IC50 value of 0.8nM[4]. Treatment with 1µM Zotarolimus for 48 hours significantly inhibited the migration of human coronary artery endothelial cells (HCAECs) and reduced the expression of pro-inflammatory cytokines[5].
In vivo, Zotarolimus treatment via intraperitoneal injection at a dose of 2mg/kg/day for 3 weeks suppressed tumor growth in the HCT-116 cell xenograft tumor mouse model[6]. Combined administration of Zotarolimus (2mg/kg/day) and 5-fluorouracil (100mg/kg/week) by intraperitoneal injection for 3 weeks significantly inhibited the progression of lung adenocarcinoma in the A549 cell xenograft mouse model and suppressed the expression of IL-1β and TNF-α[7].
References:
[1] Garcia-Touchard A, Burke S E, Toner J L, et al. Zotarolimus-eluting stents reduce experimental coronary artery neointimal hyperplasia after 4 weeks[J]. European heart journal, 2006, 27(8): 988-993.
[2] Shokati T, Drake S H, Zhao W, et al. Structural Identification of Zotarolimus (ABT-578) Metabolites Generated by Human Liver Microsomes Using Ion-Trap and High-Resolution Time-of-Flight Mass Spectrometry in Combination with the Analysis of Fragmentation Patterns[J]. Metabolites, 2023, 13(10): 1093.
[3] Burke S E, Kuntz R E, Schwartz L B. Zotarolimus (ABT-578) eluting stents[J]. Advanced drug delivery reviews, 2006, 58(3): 437-446.
[4] Chen Y W, Smith M L, Sheets M, et al. Zotarolimus, a novel sirolimus analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression[J]. Journal of cardiovascular pharmacology, 2007, 49(4): 228-235.
[5] Steinfeld D S, Liu A P, Hsu S H, et al. Comparative assessment of transient exposure of paclitaxel or zotarolimus on in vitro vascular cell death, proliferation, migration, and proinflammatory biomarker expression[J]. Journal of Cardiovascular Pharmacology, 2012, 60(2): 179-186.
[6] Chang G R, Kuo C Y, Tsai M Y, et al. Anti-cancer effects of zotarolimus combined with 5-fluorouracil treatment in HCT-116 colorectal cancer-bearing BALB/c nude mice[J]. Molecules, 2021, 26(15): 4683.
[7] Wu C F, Wu C Y, Chiou R Y Y, et al. The anti-cancer effects of a zotarolimus and 5-fluorouracil combination treatment on A549 cell-derived tumors in Balb/c nude mice[J]. International Journal of Molecular Sciences, 2021, 22(9): 4562.
Zotarolimus(ABT-578)是一种免疫抑制剂，可通过抑制亲免疫蛋白FKBP12的结合发挥作用，IC50值为2.8±0.16nM[1]。Zotarolimus与FKBP12结合形成Zotarolimus-FKBP12复合物后，能够抑制哺乳动物雷帕霉素靶蛋白（mTOR），从而调控细胞内代谢过程[2]。Zotarolimus已广泛应用于新型药物洗脱支架的研发，用于预防冠状动脉再狭窄[3]。
在体外，Zotarolimus处理48小时可抑制人冠状动脉平滑肌细胞(HCASMC)的增殖，IC50值为0.8nM[4]。使用1µM的Zotarolimus处理人冠状动脉内皮细胞(HCAECs) 48小时，能显著抑制细胞迁移并降低促炎细胞因子的表达[6]。
在体内，每日腹腔注射2mg/kg/day剂量的Zotarolimus连续3周，可抑制HCT-116细胞移植瘤小鼠模型的肿瘤生长[6]。联合使用Zotarolimus（2mg/kg/day）与5-氟尿嘧啶（100mg/kg/week）腹腔注射治疗3周，能显著抑制A549细胞移植瘤模型中肺腺癌的进展，并降低IL-1β和TNF-α的表达水平[7]。