Background
E3330 is a small-molecule inhibitor of apurinic-apyrimidinic endonuclease/redox effector factor (APE1/Ref-1) redox domain function (IC50, 50 μmol/L) [1,2].
E3330(10-30 μM, 72h) inhibits not only the growth but also the migratory abilities of pancreatic cancer cells in vitro [1].The co-incubation of E3330(30 μM, 3 h ) and cisplatin (5-20 μM, 72 h) significantly decreased cell viability compared to cisplatin alone in the human NSCLC cell line H1975 [3]. E3330 treatment prevented the functional activation of NF-κB via the alteration of APE1 subcellular trafficking and reduced IL-6 and IL-8 expression induced by TNF-α [4]. E3330 clearly suppressed secretion of inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL-6) and IL-12 and inflammatory mediators nitric oxide (NO) as well as prostaglandin E2 (PGE2) from the LPS-stimulated RAW264.7 cells [5].
E3330 (10-100 mg/kg, oral) treatment 1 hr after galactosamine challenge attenuated the liver injury. E3330 was effective when administered p.o. 6 or 12 hr after galactosamine challenge in the galactosamine-induced hepatitis model in F344 rats [6]. The injection of TNF in combination with galactosamine resulted in severe liver injury. Oral pretreatment with 100 and 300 mg/kg of E3330 30 min prior to the injection of galactosamine/TNF significantly attenuated the increase in plasma L-alanine aminotransferase and L-aspartate aminotransferase activities [7]. The estimated half-life (t1/2) of E3330 was 3.7 hours in mice [2].
参考文献:
[1]. Zou G M, Maitra A. Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration[J]. Molecular cancer therapeutics, 2008, 7(7): 2012-2021.
[2]. Fishel M L, Colvin E S, Luo M, et al. Inhibition of the redox function of APE1/Ref-1 in myeloid leukemia cell lines results in a hypersensitive response to retinoic acid-induced differentiation and apoptosis[J]. Experimental hematology, 2010, 38(12): 1178-1188.
[3]. Manguinhas R, Fernandes A S, Costa J G, et al. Impact of the APE1 redox function inhibitor E3330 in non-small cell lung cancer cells exposed to cisplatin: increased cytotoxicity and impairment of cell migration and invasion[J]. Antioxidants, 2020, 9(6): 550.
[4]. Cesaratto L, Codarin E, Vascotto C, et al. Specific inhibition of the redox activity of ape1/ref-1 by e3330 blocks tnf-α-induced activation of IL-8 production in liver cancer cell lines[J]. PLoS One, 2013, 8(8): e70909.
[5]. Jedinak A, Dudhgaonkar S, Kelley M R, et al. Apurinic/Apyrimidinic endonuclease 1 regulates inflammatory response in macrophages[J]. Anticancer research, 2011, 31(2): 379-385.
[6]. Nagakawa J, Hirota K, Hishinuma I, et al. Protective effect of E3330, a novel quinone derivative, in galactosamine-induced hepatitis in rats[J]. Journal of Pharmacology and Experimental Therapeutics, 1993, 264(1): 496-500.
[7]. Nagakawa J, Hishinuma I, Hirota K, et al. Protective effects of E3330, a novel quinone derivative, on galactosamine/tumor necrosis factor-α-induced hepatitis in mice[J]. European journal of pharmacology, 1992, 229(1): 63-67.
E3330 是脱嘌呤-脱嘧啶核酸内切酶/氧化还原效应因子 (APE1/Ref-1) 氧化还原结构域功能的小分子抑制剂（IC50，50 μmol/L）[1,2]。
E3330(10-30 μM, 72h) 在体外抑制胰腺癌细胞的生长和迁移能力[1]。E3330(30 μM, 3 h ) 和顺铂（5-20 μM，72 小时）在人 NSCLC 细胞系 H1975 [3] 中与单独使用顺铂相比显着降低了细胞活力。 E3330 治疗通过改变 APE1 亚细胞运输和减少 TNF-α 诱导的 IL-6 和 IL-8 表达来阻止 NF-κB 的功能激活[4]。 E3330 明显抑制炎症细胞因子的分泌，包括肿瘤坏死因子-α (TNF-α)、白细胞介素 (IL-6) 和 IL-12，以及来自 LPS 刺激的炎症介质一氧化氮 (NO) 和前列腺素 E2 (PGE2) RAW264.7 细胞 [5].
半乳糖胺攻击后 1 小时，E3330（10-100 mg/kg，口服）治疗减轻了肝损伤。 E3330 口服给药时有效。在 F344 大鼠的半乳糖胺诱导的肝炎模型中，半乳糖胺攻击后 6 或 12 小时 [6]。结合半乳糖胺注射 TNF 会导致严重的肝损伤。在注射半乳糖胺/TNF 前 30 分钟口服 100 和 300 mg/kg E3330 预处理可显着减弱血浆 L-丙氨酸氨基转移酶和 L-天冬氨酸氨基转移酶活性的增加[7]。 E3330 在小鼠中的估计半衰期 (t1/2) 为 3.7 小时[2]。
Protocol
| Cell experiment [1]: |
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Cell lines
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Pancreatic cancer PaCa-2 and Panc-1 cells
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Preparation Method
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Cells were were maintained at 37 ⊿in 5% CO2 and grown in Dulbecco's Modified Eagle's Medium with 10% cosmic calf serum. PaCa-2 and Panc-1 cells were treated with E3330 for 72 and 48 hours, respectively.
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Reaction Conditions
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0-135 μM for 48, 72 h
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Applications
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E3330 was found to effectively slow the growth rate of cells in a dose-dependent manner, with an ED50 of 135 and 87 μmol/L for PaCa-2 and Panc-1, respectively.
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| Animal experiment [2]: |
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Animal models
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Nonobese diabetic/severe combined immunodeficient mice (NOD/SCID) mice
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Preparation Method
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PaCa-2 cells (2.5 × 106) in 0.2 mL of DMEM media were implanted s.c. into the right flanks of NOD/SCID mice. E3330 was dissolved in 4% CremophorEL:EtOH (1:1)/saline solution or methylcellulose (0.5%). When tumor volumes were greater than 100 mm3, E3330 was administered orally twice daily, 8 hours apart, at 25 mg/kg for 10 to 12 days (5 days on 2 days off schedule). Tumors were measured biweekly and followed for approximately 6 weeks.
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Dosage form
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25 mg/kg, orally twice daily, for 10 to 12 days (5 days on 2 days off schedule)
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Applications
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In contrast to vehicle-control tumors, PaCa-2 xenografts showed a significant tumor growth delay.
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参考文献:
[1] : Fishel M L, Jiang Y, Rajeshkumar N V, et al. Impact of APE1/Ref-1 Redox Inhibition on Pancreatic Tumor GrowthAPE1/Ref-1 Redox Inhibition on Pancreatic Tumor Growth[J]. Molecular cancer therapeutics, 2011, 10(9): 1698-1708.
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