| 名稱 | AG14361 |
| 描述 | AG14361 is an effective inhibitor of PARP1 (Ki<5 nM). |
| 細胞實驗 | LoVo and SW620 colorectal cancer cells and A549 non–small-cell lung carcinoma cells are maintained in RPMI-1640 medium containing 10% fetal calf serum. Cell growth inhibition is estimated in exponentially growing LoVo, A549, and SW620 cells in 96-well plates. Cells are exposed to AG14361 (0–20 μM) alone or in the presence of 400 μM temozolomide. After 5 days of culture, these cells are fixed with 10% trichloroacetic acid and stained with sulforhodamine B. The concentration of temozolomide, topotecan, and AG14361 alone or in combination that inhibits growth by 50% (GI50) is calculated from computer-generated curves. Recovery from potentially lethal damage is measured in confluent LoVo cell cultures arrested in G1 phase to mimic the radiation-resistant quiescent cell population in tumors. Such cells are exposed to 8 Gy of γ-irradiation and then harvested and plated for colony formation assay immediately or maintained as growth-arrested confluent cultures for a 4-hour or 24-hour recovery period before harvesting and plating for the colony formation assay. Where indicated, 0.4 μM AG14361 is added 30 minutes before irradiation and is present in the recovery incubation. (Only for Reference) |
| 激酶實驗 | PARP-1 Activity Assays: The activity of full-length recombinant human PARP-1 is measured in a reaction mixture containing 20 nM PARP-1, 500 μM NAD+ plus [32P]NAD+ (0.1–0.3 μCi per reaction mixture), and activated calf thymus DNA (10 μg/mL) at 25oC; the reaction is terminated after 4 minutes by adding ice-cold 10% (wt/vol) trichloroacetic acid. The reaction product [32P]ADP-ribose incorporated into acid-insoluble material is deposited onto Whatman GF/C glass fiber filters with a Bio-Dot microfiltration apparatus and quantified with a PhosphorImager. Inhibition of PARP-1 activity by AG14361 at 0–600 nM is measured, and the Ki for AG14361 is calculated by nonlinear regression analysis. |
| 體外活性 | 在無毒劑量內,AG14361可提高伊立替康、x射線照射及替莫唑胺誘導的LoVo移植瘤生長延遲,提高2到3倍.在SW620移植瘤中, AG14361（10 mg/kg,i.p.）處理4小時以上可抑制75%以上的PARP-1活性.在攜帶LoVo移植瘤的小鼠體內,先以AG14361處理再進行統(tǒng)計學輻射,看顯著提高對放射療法的敏感性.在移植瘤中,AG14361可顯著提高血流,故可能促進藥物輸送到移植瘤. |
| 體內活性 | AG14361（0.4 μM）對癌細胞基因表達或生長無影響,但可提高替莫唑胺和拓撲替康抗增殖活性,且抑制LoVo細胞從潛在的致命γ輻射損傷中恢復,抑制達73％。AG14361（0.4 μM）對基因表達無大幅影響。在A549細胞中, AG14361（0.4 μM）在17小時后對6800種基因表達均無影響。因此,盡管0.4 μM AG14361抑制85%以上細胞PARP-1 活性,但其不影響基因表達和細胞增殖。AG14361在更高濃度會影響基因表達,但是這種影響與PARP-1受抑制無關,因為在PARP-/-和PARP-1+/+細胞中,細胞增殖一樣受影響。AG14361可增加喜樹堿誘導DNA單鏈斷裂的持久性。AG14361的效果比苯甲酰胺至少高1×103倍。AG14361對透性化SW620細胞（IC50：29 nM）和完整SW620細胞（IC50：14 nM）有抑制作用。AG14361對細胞生長的抑制作用與PARP-1抑制無關,因為在比GI50濃度低很多時(≤1 μM),對PARP-1也有最大抑制效果。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 15 mg/mL (46.82 mM), Sonication is recommended.
H2O : < 1 mg/mL (insoluble or slightly soluble)
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
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| 關鍵字 | inhibit | PARP | Inhibitor | AG14361 | poly ADP ribose polymerase |
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