TPEN is a cell-permeable, multidentate heavy metal chelator that binds zinc ions with high affinity, and has lower affinity for Mg2+ and Ca2+ [1]. TPEN depletes intracellular zinc, triggering increased ROS production, DNA damage, and caspase-dependent apoptosis, thereby inhibiting cell proliferation [2]. TPEN is primarily used in tumor therapy, hypoxia protection, and anti-infection research [3-4].
Retinal pigment epithelial cells, the cell morphology of cells exposed to TPEN (0.25-4μM; 24h) changed from a broad and flat shape to a fibrous one [5]. In Panc-1 cells, TPEN (0-6μM; 24h) significantly induced cell death by increasing reactive oxygen species (ROS) and inhibiting autophagy [6].
In mast cell-dependent mice model of allergic asthma, TPEN (10mg/kg; ip; 7d) significantly inhibited airway hyperresponsiveness and eosinophilia in bronchoalveolar lavage fluid [7]. In diabetic mice model, TPEN (5mg/kg; ip; 4 months) treatment further reduced diabetes-induced reduction in liver zinc levels [8].
References:
[1]. Taki M, Wolford J L, O'Halloran T V. Emission ratiometric imaging of intracellular zinc: design of a benzoxazole fluorescent sensor and its application in two-photon microscopy[J]. Journal of the American Chemical Society, 2004, 126(3): 712-713.
[2]. Mendivil-Perez M, Velez-Pardo C, Jimenez-Del-Rio M. TPEN induces apoptosis independently of zinc chelator activity in a model of acute lymphoblastic leukemia and ex vivo acute leukemia cells through oxidative stress and mitochondria caspase‐3‐and AIF‐dependent pathways[J]. Oxidative medicine and cellular longevity, 2012, 2012(1): 313275.
[3]. Schaefer-Ramadan S, Barlog M, Roach J, et al. Synthesis of TPEN variants to improve cancer cells selective killing capacity[J]. Bioorganic Chemistry, 2019, 87: 366-372.
[4]. Shmist Y A, Kamburg R, Ophir G, et al. N, N, N′, N′-Tetrakis (2-pyridylmethyl)-ethylenediamine improves myocardial protection against ischemia by modulation of intracellular Ca2+ homeostasis[J]. The Journal of pharmacology and experimental therapeutics, 2005, 313(3): 1046-1057.
[5]. Hyun H J, Sohn J H, Ha D W, et al. Depletion of intracellular zinc and copper with TPEN results in apoptosis of cultured human retinal pigment epithelial cells[J]. Investigative ophthalmology & visual science, 2001, 42(2): 460-465.
[6]. Yu Z, Yu Z, Chen Z B, et al. Zinc chelator TPEN induces pancreatic cancer cell death through causing oxidative stress and inhibiting cell autophagy[J]. Journal of cellular physiology, 2019, 234(11): 20648-20661.
[7]. Fukuyama S, Matsunaga Y, Zhanghui W, et al. A zinc chelator TPEN attenuates airway hyperresponsiveness and airway inflammation in mice in vivo[J]. Allergology International, 2011, 60(3): 259-266.
[8]. Zhang C, Lu X, Tan Y, et al. Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in zinc deficient mouse model[J]. PloS one, 2012, 7(12): e49257.
TPEN是一种可穿透细胞的多齿重金属螯合剂，能够高亲和力地结合锌离子，并且对Mg2+和Ca2+具有较低的亲和力 [1]。TPEN能够消耗细胞内的锌离子，从而引发ROS生成增加、DNA损伤和胱天蛋白酶依赖性细胞凋亡，从而抑制细胞增殖 [2]。TPEN主要用于肿瘤治疗、缺氧保护和抗感染研究 [3-4]。
在视网膜色素上皮细胞中，暴露于TPEN（0.25-4μM；24h）的细胞形态从宽扁平状转变为纤维状 [5]。在Panc-1细胞中，TPEN（0-6μM；24h）通过增加活性氧（ROS）和抑制自噬显著诱导细胞死亡 [6]。
在肥大细胞依赖性过敏性哮喘小鼠模型中，TPEN（10mg/kg；ip；7d）显著抑制了气道高反应性和支气管肺泡灌洗液中的嗜酸性粒细胞增多 [7]。在糖尿病小鼠模型中，TPEN（5mg/kg；ip；4个月）治疗进一步降低了糖尿病引起的肝脏锌水平降低 [8]。