Background
NVP-BEZ235 is a novel therapeutic agent that targets 2 molecules in thePI3K/Akt/mTOR (phosphatidylinositol 3-kinase) pathway, PI3K and mTOR. It is an ATP-competitive pan-class I PI3K inhibitor that is effective against p110α with hotspot mutations, and likewise inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 [1]. NVP-BEZ235 antagonizes the PI3K/mTOR signaling pathway and induces cell-cycle arrest, autophagy, and downregulation of vascular endothelial growth factor in glioma cells. NVP-BEZ235 is also an effective radiosensitizer that inhibits ataxia telangiectasia mutated (ATM) and DNA-PK catalytic subunits (DNA-PKcs), arrests cell cycle, and induces apoptosis [2].
NVP-BEZ235 treated colorectal cancer (CRC) cell lines resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (IC50 = 9.0-14.3 nM) [3]. All cell lines with PI3K-activating mutations or Pten deletions (A2780, IGROV1, MOVCAR18, OAW42, and SKOV3) were highly sensitive to NVP-BEZ235 (IC50 range 26-70 nM). In contrast, HEYC2, OV167, OV207, and OVCAR5 cells, that lack PI3K-activating mutations or Pten deletions, had an IC50 ≥ 100 nM (IC50 range 100-210 nM) for NVP-BEZ235. Overall, a statistically significant difference between the average NVP-BEZ235 IC50 for cell lines with PI3K mutations or Pten deletions (IC50 = 48.5 ± 8.1 nM) compared to cell lines that lack these mutations (IC50 = 95.9 ± 18.4 nM) [1].
Mouse model of Alzheimer's disease (AD) that expresses a mutant amyloid-β precursor protein (T41 mice) to investigate the effects of NVP-BEZ235. Ten-months-old T41 animals were treated for 14 days with NVP-BEZ235 or vehicle via oral gavage and then submitted to social memory, open field and contextual conditioned fear tests. Hippocampal slices were prepared and Aβ1-42 content, NeuN, Iba-1, CD68 and GFAP were evaluated. Tissues were further processed to evaluate cytokines levels through cytometric bead array. The treatment with NVP-BEZ235 (5 mg/kg) reduced social memory impairment in T41 mice. The drug reduced the CD68/Iba-1 ratio in CA3 region of hippocampus. NVP-BEZ235 diminished IL-10 levels in T41 mice [4].
参考文献:
[1]. C. Santiskulvong, G.E. Konecny, M. Fekete, et al. Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma. Clin. Cancer Res., 17 (2011), pp. 2373-2384
[2]: Wang WJ, Long LM, Yang N, et al. NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro. Acta Pharmacol Sin. 2013;34:681-690.
[3]. J. Roper, M.P. Richardson, W.V. Wang, L.G. Richard, W. Chen, E.M. Coffee, et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS ONE, 6 (2011), p. e25132
[4]. P.M.Q. Bellozi, G.F. Gomes, L.R. de Oliveira, et al. NVP-BEZ235 (Dactolisib) has protective effects in a transgenic mouse model of Alzheimer's disease. Frontiers in Pharmacology, 10 (2019), p. 1345
NVP-BEZ235 是一种新型治疗剂，靶向 PI3K/Akt/mTOR（磷脂酰肌醇 3-激酶）通路中的 2 个分子，即 PI3K 和 mTOR。它是一种 ATP 竞争性泛 I 类 PI3K 抑制剂，对具有热点突变的 p110α 有效，同样抑制哺乳动物雷帕霉素靶标复合物 1 (mTORC1) 和 mTORC2 [1]。 NVP-BEZ235 拮抗 PI3K/mTOR 信号通路并诱导细胞周期停滞、自噬和神经胶质瘤细胞中血管内皮生长因子的下调。 NVP-BEZ235 也是一种有效的放射增敏剂，可抑制共济失调性毛细血管扩张症突变 (ATM) 和 DNA-PK 催化亚基 (DNA-PKcs)、阻滞细胞周期并诱导细胞凋亡[2]。
NVP-BEZ235 处理的结直肠癌 (CRC) 细胞系导致短暂的 PI3K 阻断、mTORC1/mTORC2 信号持续降低以及细胞活力相应降低（IC50 = 9.0-14.3 nM ) [3]。所有具有 PI3K 激活突变或 Pten 缺失的细胞系（A2780、IGROV1、MOVCAR18、OAW42 和 SKOV3）对 NVP-BEZ235 高度敏感（IC50 范围 26-70 nM）。相反，缺乏 PI3K 激活突变或 Pten 缺失的 HEYC2、OV167、OV207 和 OVCAR5 细胞的 IC50 ≥ 100 nM（IC50 范围为 100- 210 nM）对于 NVP-BEZ235。总体而言，与细胞系相比，具有 PI3K 突变或 Pten 缺失的细胞系的平均 NVP-BEZ235 IC50（IC50 = 48.5 ± 8.1 nM）之间存在统计学显着差异缺乏这些突变 (IC50 = 95.9 ± 18.4 nM) [1]。
阿尔茨海默病 (AD) 小鼠模型表达了一种突变型淀粉样蛋白-β 前体蛋白（T41 小鼠），以研究 NVP-BEZ235 的作用。 10 个月大的 T41 动物通过口服强饲法用 NVP-BEZ235 或载体治疗 14 天，然后进行社交记忆、开放场和情境条件恐惧测试。制备海马切片并评估Aβ1-42含量、NeuN、Iba-1、CD68和GFAP。进一步处理组织以通过细胞计数珠阵列评估细胞因子水平。用 NVP-BEZ235 (5 mg/kg) 治疗可减少 T41 小鼠的社交记忆障碍。该药降低了海马CA3区的CD68/Iba-1比值。 NVP-BEZ235 降低了 T41 小鼠的 IL-10 水平[4]。
Protocol
| Cell experiment [1]: |
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Cell lines
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Glioma stem cells
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Preparation Method
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NVP-BEZ235 was dissolved in DMSO to obtain a stock concentration of 10 mmol/L, which was aliquoted and stored at -20 °C and diluted to the desired final concentration in DMEM/F12 at the time of use. The GSC cells were treated with various concentrations of NVP-BEZ235 for 24, 48, or 72 h.
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Reaction Conditions
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10,20,40,80,160,320μM for 24, 48, or 72 h
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Applications
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NVP-BEZ235 treatment significantly increased radiation sensitivity in GSCs, and the inhibition of autophagy by 3-MA blocked NVP-BEZ235-mediated radiosensitization.
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| Animal experiment [2]: |
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Animal models
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male transgenic Tg (Thy1-APPSweLon) 41Ema (T41) mice and their wild-type (WT) littermates.
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Preparation Method
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Animals were treated by oral gavage with 5 or 25 mg/kg of NVP-BEZ235, diluted in 1-metyl 2-pirrolidone 10% in PEG 300, or vehicle, once a day for 14 days. According to the genotype (WT or T41) and the treatment (NVP-BEZ235 or vehicle), the animals were divided into five groups: WT + Vehicle, WT + NVP-BEZ235 25 mg/kg (WT + BEZ 25), T41 + Vehicle, T41 + NVP-BEZ235 5 mg/kg (T41 + BEZ 5), and T41 + NVP-BEZ235 25 mg/kg (T41 + BEZ 25).
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Dosage form
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5 or 25 mg/kg, oral
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Applications
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BEZ 5 mg/kg significantly reversed this memory impairment in T41 mice. Memory loss is the main sign of Alzheimer's disease (AD)
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参考文献:
[1]: Wang WJ, Long LM, Yang N, et al. NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro. Acta Pharmacol Sin. 2013;34:681-690.
[2]: P.M.Q. Bellozi, G.F. Gomes, L.R. de Oliveira, et al. NVP-BEZ235 (Dactolisib) has protective effects in a transgenic mouse model of Alzheimer's disease. Frontiers in Pharmacology, 10 (2019), p. 1345
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